Ganaxolone for use in treatment of status epilepticus

ABSTRACT

This invention relates to methods for treating status epilepticus by administering to the subject in need thereof an intravenous bolus of ganaxolone and a continuous intravenous infusion of a neurosteroid. The method provides SE suppression and continued suppression of SE.

The present application claims the benefit of U.S. ProvisionalApplication No. 62/882,648 filed on Aug. 5, 2019, the entire contents ofwhich are incorporated herein by reference.

1. BACKGROUND

Status epilepticus (“SE”) is a life-threatening neurological emergencyassociated with significant morbidity and mortality (Betjemann andLowenstein, (2015) The Lancet Neurology, 14(6):615-624). In fact, it isthe second most common neurologic emergency in the United States withapproximately 150,000 cases per year and 55,000 associated deaths peryear (Moghasddasi et al., (2015) J. Epilepsy Res., 5(1):13-16).

SE is manifested by prolonged seizure activity, typically persistingmore than 5 minutes, or recurrent seizures without recovery ofconsciousness between seizures. Id. SE requires aggressive treatment tostop the seizure and prevent neurological damage, including neuronaldeath. SE becomes more difficult to control as its duration increases,and prolonged SE and refractoriness to treatment are associated withpoor prognosis (Cherian & Thomas (2009), Ann. Indian. Acad. Neurol.,12(3):140-153). Goals of treatment are rapid seizure cessation,maintenance of seizure control, preventing progression to anestheticsand avoiding further medical complications. Id.

Current treatment protocols for SE take a three-stage approach (Shorvonand Ferlisi (2011), Brain, 134(10)-2802-2818). The first-line treatmentis typically with benzodiazepines (e.g., diazepam, lorazepam, andmidazolam) (Trinka and Kälviäinen (2017), Seizure, 44:65-73; Glauser etal., (2016), Epilepsy Curr. 26(1):48-61). However, benzodiazepines areineffective in about 35%-45% of cases and are associated withcardiovascular and respiratory side effects. Id. If SE continues despitetreatment with benzodiazepines, other anti-seizure medications (e.g.,fosphenytoin, levetiracetam, and valproate) are administeredintravenously (IV) as second-line treatment. Id. In instances when SEcontinues despite first-line and second-line treatment, also calledrefractory SE, intravenous anesthetics (e.g., thiopental, propofol, andmidazolam) are used as third-line treatment. Id. About 31%-41% ofpatients with SE develop refractory SE. The use of third-line agentsproduces iatrogenic coma, which necessitates protection of the airwaysby intubation and mechanical ventilation. Further, use of anesthetics isassociated with high morbidity and approximately 35% mortality. If SEcontinues despite induction of iatrogenic coma, it is termedsuper-refractory SE. A summary of available therapies for SE, includingtheir adverse effects, is provided in table 1.

TABLE 1 Summary of Available Therapies in Status Epilepticus TherapyAdverse Effects and Other Clinical Considerations First-line TherapyBenzodiazepines Respiratory depression and hypotension Second-lineTherapy Fosphenytoin Cardiovascular risk associated with rapid infusionand must be delivered slowly with cardiac monitoring for toxicityincluding severe hypotension and cardiac arrhythmias Phenytoin QTinterval prolongation, arrhythmias, and purple glove syndrome; narrowtherapeutic range Valproic acid Hepatotoxic effects, thrombocytopenia,pancreatitis, and hyperammonemia Levetiracetam Significantly lessefficacious than valproic acid and phenytoin Phenobarbital Respiratoryand circulatory depression Lacosamide Cardiac rhythm and conductionabnormalities Third-line Therapy Propofol Hypotension, respiratorydepression, and propofol infusion syndrome; hemodynamic complicationsdue to intubation Midazolam Respiratory depression and hypotension;hemodynamic complications due to intubation Pentobarbital Respiratorydepression, hypotension, and bradycardia; hemodynamic complications dueto intubation

At best, current treatments effectively control moderately severe SE inonly about 50% of patients. In severe SE, the success rate is furtherreduced (Shorvon and Ferlisi, (2011), Brain, 134(1):2802-2818).Moreover, some recent attempts to develop new treatments have failed.For example, brexanolone (SAGE-547), a synthetic form of endogenousallopregnanolone, failed to show efficacy over placebo in a randomized,double-blind, placebo-controlled trial for the treatment insuper-refractory SE. (Sage Pharmaceuticals press release Sep. 12, 2017,www.businesswire.com/news/home/20170912005509/en/Sage-Therapeutics-Reports-Top-Line-Results-Phase-3).Accordingly, there is a significant unmet need for effective therapiesfor treating SE.

2. SUMMARY

This disclosure relates to a method for treating SE. SE is an extremelycomplicated condition to treat and developing new treatments for SE hasbeen significantly challenging and largely unsuccessful. As noted above,conventional therapies are ineffective in more than 50% of patients.Attempts to develop new treatments for SE have generally failed. Forexample, brexanolone (i.e., allopregnanolone) failed to show efficacyover placebo in a double blind, placebo-controlled Phase 3 trial inpatients with super refractory SE.

As further described and exemplified herein, the inventors believed thatganaxolone could provide effective therapy for SE. But, given thecomplexity and difficulties in treating SE, and failure of prior studiesto show efficacy, the inventors expected that a high drug exposure forat least 4 days, followed by a maintenance dose for at least about 1day, would be required for effective treatment of SE. Contrary to theseexpectations, the inventors surprisingly discovered that administeringganaxolone as a bolus plus continuous infusion to maintain plasmaconcentration of ganaxolone at a much lower than expected serum levelfor at least about 8 hours (or possibly at least about 4 hours in somesubjects) resulted in rapid and continued suppression of SE. As furtherdescribed and exemplified herein, continued suppression of SE wasachieved when the continuous infusion maintains a plasma concentrationof ganaxolone of about 500 ng/ml or higher for a target concentrationperiod of at least about 8 hours or at least about 12 hours (although insome patients 4 hours can be sufficient), in the patients that werestudied.

Accordingly, this disclosure relates to a method for effectivelytreating SE that provides rapid suppression of SE, sustained efficacy(i.e., prevents SE-relapse and provides for continued suppression ofSE), and improved safety.

The methods disclosed herein comprise administering to a subject in needthereof a therapeutically effective amount of a neurosteroid, preferablyganaxolone, as an intravenous bolus and a continuous intravenousinfusion. The intravenous bolus is administered in an amount to suppressSE. Suppression of SE reduces seizure burden. Typically a ganaxoloneplasma concentration of about 500 ng/ml to about 1000 ng/ml issufficient to suppress SE. For example, to achieve a ganaxolone plasmaconcentration level of 500 ng/ml to about 1000 ng/ml, an infusion ofabout 5 mg to about 40 mg of ganaxolone can be infused into the subjectat the initiation the intravenous bolus. Preferably, about 30 mg ofganaxolone is infused into the subject at the initiation of theintravenous bolus or during the intravenous bolus The intravenous boluscan be administered (i.e., infused) into the subject for about 1 minuteto about 5 minutes.

The continuous intravenous infusion of ganaxolone is administered for atarget concentration period in an amount sufficient for continuedsuppression of SE. Clinically, continued suppression of SE is areduction in seizure burden.

The continuous intravenous infusion of ganaxolone is initiatedperiprocedural with the intravenous bolus. The continuous intravenousinfusion is generally administered concurrently with the administrationof the intravenous bolus. In some cases, the continuous intravenousinfusion can be initiated before or after the intravenous bolus.

Continued suppression of SE is achieved when the continuous infusionmaintains a plasma concentration of ganaxolone of about 500 ng/ml orhigher throughout a target concentration period. The continuous infusionis administered throughout the treatment period, which include thetarget concentration period, during which the subject's plasmaconcentration of ganaxolone is maintained at or above a targetconcentration, such as about 425 ng/ml, about 45 ng/ml, about 475 ng/mlor preferably about 500 ng/ml. Although, it is recognized that a plasmaconcentration of about 425 ng/ml, at least about 450 ng/ml, or at leastabout 475 ng/ml or is preferably at least about 500 ng/ml is sufficientto maintain continued SE suppression. Generally, it is desired that theganaxolone plasma concentration is not higher than about 1000 ng/ml.This is because a ganaxolone plasma concentration of higher than 1000ng/ml can induce anesthesia, which is not a desired effect of thetreatment. The target concentration period is typically at least about 8hours or at least 12 hours. In some cases, it is possible that thetarget concentration can be at least about 4 hours. Typically, theamount of ganaxolone administered to the subject per hour by continuousintravenous infusion during the target concentration period can beincreased or decreased to maintain continued suppression of SE, but issufficient to maintain a ganaxolone plasma concentration of at leastabout 500 ng/ml.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased over a period of about24 hours from the initiation of the continuous intravenous infusion. Theamount of ganaxolone administered to the subject per hour by continuousintravenous infusion can be decreased about 2 hours and/or about 10hours to about 14 hours after the initiation of the continuousintravenous infusion. The amount of ganaxolone administered to thesubject per hour by continuous intravenous infusion is preferablydecreased about 2 hours after the initiation of the continuousintravenous infusion and then about 10 hours to about 14 hours after theinitiation of the continuous intravenous infusion.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased by about 50%, relativeto the amount administered per hour at the initiation of the continuousintravenous infusion, about 2 hours after the initiation of thecontinuous intravenous infusion. The amount of ganaxolone administeredto the subject per hour by continuous intravenous infusion can bedecreased by about 75%, relative to the amount administered per hour atthe initiation of the continuous intravenous infusion, about 10 hours toabout 14 hours after the initiation of the continuous intravenousinfusion. The amount of ganaxolone administered to the subject per hourby continuous intravenous infusion can be decreased by about 50%,relative to the amount administered per hour at the initiation of thecontinuous intravenous infusion, about 2 hours after the initiation ofthe continuous infusion, and then by about 75%, relative to the amountadministered per hour at the initiation of the continuous intravenousinfusion, about 10 hours to about 14 hours after the initiation of thecontinuous infusion.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased by about 50%, relativeto the rate given during the target concentration period at 2 to 12hours after initiation of the infusion. After another 12 to 24 hoursafter the initiation of the continuous intravenous, the continuousintravenous infusion can again be decreased by half, or 75% of thetarget concentration period infusion rate.

About 20 mg of ganaxolone per hour to about 80 mg of ganaxolone per hourcan infused into the subject during the continuous infusion treatmentperiod. In general, about 80 mg of ganaxolone per hour can be infusedinto the subject at the initiation of the continuous intravenousinfusion. After about 2 hours, amount of ganaxolone can then bedecreased to about 40 mg of ganaxolone per hour then to about 20 mg ofganaxolone per hour during the treatment period. In some instances,about 80 mg of ganaxolone can be administered to the subject by thecontinuous intravenous infusion from initiation and for about 2 hoursthereafter, then about 40 mg of ganaxolone per hour can be administeredto the subject by continuous intravenous infusion starting about 2 hoursafter initiation and for about 2 hours to about 10 hours thereafter,then about 20 mg of ganaxolone per hour can be administered to thesubject by continuous intravenous infusion starting about 12 hours afterinitiation and for about 12 hours to about 24 hours thereafter.

The amount of ganaxolone administered to the subject per by continuousintravenous infusion can be increased after about 24 hours from theinitiation of the intravenous infusion. In general, the amount ofganaxolone administered per hour by continuous intravenous infusion canbe increased by up to by about 45%, relative to the amount administeredper hour starting after about 24 hours after initiation of thecontinuous intravenous infusion. For instance, the amount of ganaxoloneinfused into the subject by continuous intravenous infusion can beincreased up to about 45 mg of ganaxolone per hour, but preferably doesnot exceed 45 mg, starting about 24 hours after the initiation and forup to about 12 hours thereafter. The amount of ganaxolone can beincreased for a period of up to 12 hours.

The treatment period of the continuous intravenous infusion can be for aperiod of about 36 hours, about 48 hours, about 72 hours, or about 96hours after the initiation of the intravenous infusion. Preferably, thetreatment period is for a period of at least about 8 hours to about 36hours after the initiation of the continuous intravenous infusion.

The continuous intravenous infusion is typically followed by a taperingperiod. The taper period generally starts at about 36 hours from theinitiation of the continuous intravenous infusion. During the taperperiod the continuous intravenous infusion of ganaxolone issystematically decreased, typically by reducing the amount of ganaxolonethat is administered to the subject by about one third every four hoursuntil the subject no longer requires ganaxolone.

The methods disclosed herein are suitable to treat any form of SE. Forexample, generalized convulsive SE, non-convulsive SE, refractory SE,and super refractory SE. The method is particularly useful for treatingrefractory SE. The method can also be used to treat subjects that havefailed first-line treatment (e.g., benzodiazepine), second-linetreatment (e.g. fosphenytoin, valproic acid or levetiracetam), and/orthird-line treatment (thiopental, midazolam, pentobarbital, orpropofol). During the treatment, the subject can be monitored for plasmaconcentration of ganaxolone and using EEG for seizure activity.

The ganaxolone formulation used in the methods disclosed hereinpreferably comprises sulfobutylether-β-cyclodextrin.

To summarize, an exemplary method of treating SE includes administeringa subject an intravenous bolus dose of ganaxolone of about 5 to about 40mg, preferably about 30 mg, over a period of about 1 to about 5 minutes,typically about 3 minutes, to achieve a short term increase inganaxolone plasma concentration of about 800 ng/ml to about 1000 ng/ml.The intravenous bolus suppresses SE. Concurrently with the intravenousbolus or after the intravenous bolus, the subject is administered acontinuous intravenous infusion. The continuous intravenous infusionprovides continued suppression of SE. Continued suppression of SE isachieved when the continuous intravenous infusion maintains a plasmaconcentration of ganaxolone of about 500 ng/ml or higher for a targetconcentration period. The target concentration period is typically for aperiod of at least about 8 hours or at least about 12 hours. Although,in some cases, at least about 4 hours may be a sufficient targetconcentration period. During the target concentration period, the amountof ganaxolone infused can be increased and/or decreased to maintain thedesired plasma ganaxolone concentration. The amount of ganaxoloneadministered to the subject per hour is typically decreased by about 50%relative to the amount administered per hour at the initiation of thecontinuous infusion about 2 hours about the initiation of the continuousintravenous infusion. The amount of ganaxolone administered to thesubject per hour can then be decreased by 75% relative to the amountadministered at the initiation of the continuous intravenous infusion.The continuous intravenous infusion is typically followed by a taperingperiod.

The methods disclosed herein comprise administering a therapeuticallyeffective amount of ganaxolone to reduce or eliminate seizure activityand/or reduce or eliminate convulsions and/or completely suppressesstatus epilepticus (i.e., suppress EEG seizure activity and convulsions)in the subject. In certain embodiments, the therapeutically effectiveamount of ganaxolone to reduce or eliminate seizure activity and/orcompletely suppresses status epilepticus in the subject is the amountthat provides and maintains a plasma concentration of ganaxolone ofabout 50 ng/ml to about 3500 ng/ml in the subject over a time periodsufficient to reduce or eliminate seizure activity and/or reduce oreliminate convulsions and/or completely suppresses status epilepticus inthe subject. In certain embodiments, the plasma concentration of about50 mg/ml to about 3500 ng/ml is provided by (i) administering a bolus(e.g., from about 5 mg to about 100 mg, from about 25 mg to about 60 mg,or from about 25 mg to about 30 mg) of ganaxolone over about 1 to about5 minutes intravenously; (ii) administering a continuous intravenousinfusion of ganaxolone at a rate between about 5 mg/hour and about 130mg/hour (e.g., from about 5 mg/hour to about 85 mg/hour) for about 8hours to about 120 hours (e.g., for about 10 hours to about 96 hours),the continuous intravenous infusion starting at about the time of thebolus injection or a short time thereafter (e.g., within about 30 min);and (iii) lowering the rate of intravenous infusion rate over about 12hours to about 24 hours (e.g., over 12 hours, about 10 hours, about 14hours, about 16 hours, about 18 hours, or about 20 hours) before thecontinuous infusion is stopped. In certain embodiments, the plasmaconcentration of about 50 mg/ml to about 3500 ng/ml is provided by (i)administering a bolus (e.g., from about 5 mg to about 100 mg, from about25 mg to about 60 mg, or from about 25 mg to about 30 mg) of ganaxoloneover about 1 to about 5 minutes intravenously; (ii) administering acontinuous intravenous infusion of ganaxolone at a rate between about 5mg/hour and about 130 mg/hour (e.g., from about 5 mg/hour to about 85mg/hour) for about 24 hours to about 120 hours (e.g., for about 48 hoursto about 96 hours), the continuous intravenous infusion starting atabout the time of the bolus injection or a short time thereafter (e.g.,within about 30 min); and (iii) lowering the rate of intravenousinfusion rate over about 10 hours to about 24 hours (e.g., over 10hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours,or about 20 hours) before the continuous infusion is stopped. In someembodiments, a portion of the therapeutically effective amount (e.g.,from about 5 mg to about 100 mg, from about 10 mg to about 90 mg, fromabout 15 mg to about 80 mg, from about 20 mg to about 70 mg, from about25 mg to about 60 mg, etc.) is administered via a bolus intravenousinjection, and the remaining portion of the therapeutically effectiveamount is administered via a continuous intravenous infusion. In someembodiments, for subjects weighing 40 kg or more, from about 5 mg toabout 100 mg (e.g., from about 10 mg to about 90 mg, from about 15 mg toabout 80 mg, from about 20 mg to about 70 mg, from about 25 mg to about60 mg, etc.) of ganaxolone may be administered via the bolus intravenousinjection, and the remainder of dose is administered via an intravenousinfusion at a rate greater than about 10 mg/hour, 15 mg/hour, 20 mg/houror 25 mg/hour for about 1 hour to about 120 hours. In some embodiments,the continuous intravenous infusion is at a rate from about 5 mg/hour toabout 130 mg/hr, about 5 mg/hour to about 120 mg/hour, from about 5mg/hour to about 110 mg/hr, from about 5 mg/hour to about 100 mg/hr,from about 5 mg/hour to about 90 mg/hr, or from about 5 mg/hour to about85 mg/hr for about 1 hour to about 120 hours. In some embodiments, thecontinuous intravenous infusion is at a rate from about 50 mg/hr toabout 130 mg/hr for at least 1 hour. In some embodiments, thetherapeutically effective dose, or a portion thereof, is administeredintravenously at a rate from about 40 mg/hour to about 140 mg/hour forabout 1 hour to about 4 hours; thereafter, at a rate from about 20mg/hour to about 70 mg/hour for about 1 hour to about 4 hours;thereafter, at a rate from about 10 mg/hour to about 35 mg/hour forabout 1 hour to about 4 hours; thereafter, at a rate from about 10mg/hour to about 30 mg/hour for about 1 hour to about 96 hours; and,thereafter at about 15 mg/hour to about 35 mg/hour for about 1 hour toabout 96 hours. In some embodiments, after the administration at therate from about 15 mg/hour to about 35 mg/hour for about 1 hour to about96 hours, the rate is reduced by about 10% to about 50% every 1 hour to12 hours (e.g., the rate may be reduced from about 15% to about 30%every 4 hours to 8 hours). In some of these embodiments, ganaxolone isadministered at about 18 mg/hour, about 20 mg/hour, about 22 mg/hour;about 25 mg/hour, about 28 mg/hour, about 30 mg/hour, about 35 mg/hour,about 40 mg/hour, about 45 mg/hour, about 50 mg/hour, about 60 mg/hour,about 65 mg/hour, or about 70 mg/hour, for at least about 1 hour of theadministration. For subjects weighing less than 40 kg, in someembodiments, a bolus dose from about 0.07 mg/kg to about 1.43 mg/kg(e.g., from about 0.125 mg/kg to about 0.4 mg/kg) is administered (over1 to 5 minutes); and, thereafter, via a continuous infusion from about0.8 mg/kg/hour to about 2 mg/kg/hour for about 1 to 3 hours; followed bya continuous infusion at a rate from about 0.6 mg/kg/hour to about 1mg/hr for about 4 to 8 hours; and, thereafter, followed by a continuousinfusion at a rate from about 0.15 mg/kg/hour to about 0.4 mg/kg/hourfor 13 to 19 hours. At the end of the 24 hours of continuous infusion,the infusion rate may be increased to, e.g., a rate from about 0.2mg/kg/hour to about 0.6 hour for 24 to 48 hours or 24 to 96 hours.

This disclosure is also directed to a method of treating statusepilepticus (e.g., a generalized convulsive status epilepticus,non-convulsive status epilepticus, early status epilepticus, establishedstatus epilepticus, refractory status epilepticus, or super-refractorystatus epilepticus), comprising administering a therapeutic dose ofganaxolone to a subject experiencing status epilepticus in a mannerwhich provides a plasma concentration of ganaxolone of about 50 ng/ml toabout 3500 ng/ml over a time period of about 24 hours to about 120hours, and from about 2 to 5 peaks in the plasma concentration ofganaxolone during said 24 hours to about 120 hours. In certainembodiments, a portion of the therapeutic dose is administered via anintravenous infusion at a rate from about 20 mg/hour to about 140mg/hour for about 4 hours to about 120 hours, a ganaxolone plasma levelfrom about 800 ng/ml to about 1600 ng/ml is maintained for about 1 hourto about 96 hours, and a portion of the dose is administered via a bolusinjection. For subjects weighing 40 kg or more, the bolus injection maycomprise, e.g., from about 5 mg to about 100 mg ganaxolone, and theamount of ganaxolone delivered via an intravenous infusion may be, e.g.,from about 450 mg to about 3000 mg. In some embodiments, from about 450mg to about 1000 mg of ganaxolone is administered over each 24 hours ofsaid 24 hours to about 120 hours. For subjects weighing less than 40 kg,the bolus injection may comprise, e.g., from about 0.25 mg to about 16mg, and from about 100 mg to about 600 mg of ganaxolone may beadministered over each 24 hours of the intravenous infusion.

This disclosure is also directed to a method of treating statusepilepticus (e.g., generalized convulsive status epilepticus,non-convulsive status epilepticus, early status epilepticus, establishedstatus epilepticus, refractory status epilepticus, or super-refractorystatus epilepticus) comprising administering intravenously atherapeutically effective dose of ganaxolone, or a portion thereof, toreduce or eliminate seizure activity and/or reduce or eliminateconvulsions and/or completely suppresses status epilepticus in thesubject experiencing status epilepticus over a time period from about 1hours to about 120 hours, from about 2 hours to about 100 hours, fromabout 3 hours to about 100 hours, from about 4 hours to about 100 hours,from about 4 hours to about 96 hours (e.g., via a continuous intravenousinfusion), wherein the intravenous infusion is started after a bolusdose from about 5 mg to about 100 mg (e.g., about 6 mg, 8 mg, 10 mg, 12mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, 50 mg, 52mg, 54 mg, 56 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95mg, 96 mg, 97 mg, 98 mg, or 99 mg) is intravenously administered to thesubject (e.g., from about 1 second to about 1 hour, from about 1 secondto about 45 minutes, from about 1 second to about 30 minutes, from about1 second to about 15 minutes, from about 1 second to about 10 minutes,from about 1 second to about 5 minutes or from about 2 seconds to about3 minutes after the bolus dose). In some of the these embodiments, thebolus dose is from about 5 mg to about 90 mg, from about 5 mg to about80 mg, form about 5 mg to about 70 mg, from about 5 mg to about 60 mg,from about 5 mg to about 50 mg, from about 5 mg to about 40 mg, or formabout 5 mg to about 30 mg.

This disclosure is further directed to a method of treating a subjectexperiencing status epilepticus (e.g., a generalized convulsive statusepilepticus, non-convulsive status epilepticus, early statusepilepticus, established status epilepticus, refractory statusepilepticus, or super-refractory status epilepticus) comprisingadministering intravenously from about 450 mg to about 3000 mgganaxolone over a time period from about 4 hours to about 120 hours at arate sufficient to reduce or eliminate seizure activity and/or reduce oreliminate convulsions and/or completely suppresses status epilepticus inthe subject. In certain embodiments, the rate is greater than about 10mg/hour, 15 mg/hour, 20 mg/hour, 25 mg/hour, or 30 mg/hour. In someembodiments from about 5 mg to about 100 mg of ganaxolone isadministered via a bolus intravenous injection, and the remainder ofdose is administered via a continuous intravenous infusion at a rategreater than about 25 mg/hour for a time period from about 1 hour toabout 120 hours.

This disclosure is also directed to a method of treating statusepilepticus (e.g., a generalized convulsive status epilepticus,non-convulsive status epilepticus, early status epilepticus, establishedstatus epilepticus, refractory status epilepticus, or super-refractorystatus epilepticus) in a subject comprising administering from about 1gram to about 100 grams (e.g., from about 20 grams to about 70 grams,from about 25 grams to about 65 grams, from about 30 grams to about 60grams, from about 35 grams to about 55 grams, etc.)sulfobutylether-β-cyclodextrin to the subject per day in a formulationcomprising ganaxolone.

This disclosure is further directed to a method of treating a subjectexperiencing status epilepticus (e.g., a generalized convulsive statusepilepticus, non-convulsive status epilepticus, early statusepilepticus, established status epilepticus, refractory statusepilepticus, or super-refractory status epilepticus) comprisingadministering intravenously to the subject a formulation comprisingganaxolone and sulfobutylether-β-cyclodextrin in a weight ratio fromabout 1:50 to about 1:75, wherein from about 450 mg to about 1000 mg ofganaxolone and from about 1 gram to about 100 gramssulfobutylether-β-cyclodextrin is administered per day. In someembodiments, the weight ratio is about 1:60, about 1:65 or about 1:70.

This disclosure is further directed to a method of treating a subjectexperiencing status epilepticus (e.g., a generalized convulsive statusepilepticus, non-convulsive status epilepticus, early statusepilepticus, established status epilepticus, refractory statusepilepticus, or super-refractory status epilepticus) comprisingadministering intravenously to the subject a formulation comprisingganaxolone and sulfobutylether-β-cyclodextrin in a weight ratio fromabout 1:50 to about 1:75 at a rate and for a duration sufficient toprovide plasma concentration of ganaxolone of about 50 ng/ml to about3500 ng/ml over a time period of about 24 hours to about 120 hours. Insome of these embodiments, the weight ratio ganaxolone andsulfobutylether-β-cyclodextrin is about 1:51, about 1:52, about 1:53,about 1:54, about 1:55, about 1:56, about 1:57, about 1:58, about 1:59,about 1:60, about 1:61, about 1:62, about 1:63, about 1:64, about 1:65,about 1:66, about 1:67, about 1:68, about 1:69, about 1:70, about 1:71,or about 1:72.

In an additional aspect, the method of treating status epilepticus(e.g., a generalized convulsive status epilepticus, non-convulsivestatus epilepticus, early status epilepticus, established statusepilepticus, refractory status epilepticus, or super-refractory statusepilepticus) comprises administering ganaxolone via an intravenousinfusion at a rate that is varied during administration from about 10mg/hour to about 150 mg/hour, about 15 mg/hour to about 150 mg/hour orabout 20 mg/hour to about 150 mg/hour. In some embodiments, thetherapeutically effective dose, or a portion thereof, is administeredparenterally at a rate from about 40 mg/hour to about 140 mg/hour forabout 1 hour to about 4 hours; then, at a rate from about 20 mg/hour toabout 70 mg/hour for about 1 hour to about 4 hours; then, at a rate fromabout 10 mg/hour to about 35 mg/hour for about 1 hour to about 4 hours;then, at a rate from about 10 ng/hour to about 30 mg/hour for about 1hour to about 96 hours; and, then, at a rate from about 15 mg/hour toabout 35 mg/hour for about 1 hour to about 96 hours. In someembodiments, after the administration at the rate from about 15 mg/hourto about 35 mg/hour for about 1 hour to about 96 hours, the rate isreduced by about 10% to about 50% every 1 hour to 12 hours (e.g., therate may be reduced from about 15% to about 30% every 4 hours to 8hours). In some of these embodiments, ganaxolone may be administered ata rate of at least about 18 mg/hour, about 20 mg/hour, about 22 mg/hour;about 25 mg/hour, about 28 mg/hour, about 30 mg/hour, about 35 mg/hour,about 40 mg/hour, about 45 mg/hour, about 50 mg/hour, about 60 mg/hour,about 65 mg/hour, or about 70 mg/hour, for at least about 1 hour of theadministration. In certain embodiments, a bolus dose of ganaxolone isadministered intravenously before the start of the intravenous infusion.The bolus dose of ganaxolone may comprise, e.g., from about 5 mg toabout 100 mg ganaxolone. In certain embodiments, one or more additionalbolus doses of ganaxolone are administered intravenously before, duringor after the intravenous infusion. The additional bolus dose maycomprise, e.g., from about 5 mg to about 100 mg ganaxolone.

This disclosure is also directed in part to a method of treating statusepilepticus (e.g., a generalized convulsive status epilepticus,non-convulsive status epilepticus, early status epilepticus, establishedstatus epilepticus, refractory status epilepticus, or super-refractorystatus epilepticus) comprising administering ganaxolone over a timeperiod from about 2 hours to about 120 hours, from about 2 hours toabout 100 hours, from about 3 hours to about 100 hours, from about 4hours to about 100 hours, from about 4 hours to about 96 hours, fromabout 5 hours to about 96 hours, from about 6 hours to about 96 hours,from about 6 hours to about 90 hours, from about 6 hours to about 88hours, or from about 10 hours to about 72 hours to a subjectexperiencing status epilepticus in an amount and at a rate sufficient toprovide a plasma concentration of ganaxolone from about 50 ng/ml toabout 3500 ng/ml, from about 75 ng/ml to about 3250 ng/ml, from about100 ng/ml to about 3000 ng/ml, from about 125 ng/ml to about 2750 ng/ml,from about 150 ng/ml to about 2500 ng/ml, from about 175 ng/ml to about2250 ng/ml, from about 200 ng/ml to about 2200 ng/nil, about 250 ng/mlto about 2150 ng/ml, from about 300 ng/ml to about 2100 ng/ml, fromabout 350 ng/ml to about 2100 ng/ml, from about 400 ng/ml to about 2100ng/ml, or from about 450 ng/ml to about 2100 ng/ml, from about 500 ng/mlto about 2000 ng/ml, from about 500 ng/ml to about 1800 ng/ml, fromabout 500 ng/ml to about 1600 ng/ml, from about 500 ng/ml to about 1500ng/ml, from about 600 ng/ml to about 1400 ng/ml, from about 600 ng/ml toabout 1300 ng/ml, from about 650 ng/ml to about 1200 ng/ml, from about700 ng/ml to about 1200 ng/ml, from about 750 ng/ml to about 1100 ng/ml,from about 800 ng/ml to about 1100 ng/ml for a time period from about 30min to about 120 hours (e.g., for about 1 hour, 3 hours, 5 hours, 7hours, 9 hours, 11 hours, 13 hours, 15 hours, 17 hours, 19 hours, 21hours, 23 hours, 25 hours, 27 hours, 29 hours, 31 hours, 33 hours, 35hours, 37 hours, 39 hours, 41 hours, 43 hours, 45 hours, 47 hours, 49hours, 51 hours, 53 hours, 55 hours, 57 hours, 59 hours, 61 hours, 63hours, 65 hours, 67 hours, 69 hours, 71 hours, 73 hours, 75 hours, 77hours, 79 hours, 81 hours, 83 hours, 85 hours, 87 hours, 89 hours, 91hours, 93 hours, or 95 hours).

The present disclosure is also directed in part to a method of treatingstatus epilepticus (e.g., a generalized convulsive status epilepticus,non-convulsive status epilepticus, early status epilepticus, establishedstatus epilepticus, refractory status epilepticus, or super-refractorystatus epilepticus) comprising administering a bolus dose of ganaxoloneintravenously in an amount sufficient to achieve a maximum plasmaganaxolone concentration (Cmax) from about 50 ng/ml to about 3500 ng/ml,from about 75 ng/ml to about 3250 ng/ml, from about 100 ng/ml to about3000 ng/ml, from about 125 ng/ml to about 2750 ng/ml, from about 150ng/ml to about 2500 ng/ml, from about 175 ng/ml to about 2250 ng/ml,from about 200 ng/ml to about 2200 ng/ml, from about 250 ng/ml to about2150 ng/ml, from about 300 ng/ml to about 2100 ng/ml, from about 350ng/ml to about 2100 ng/ml, from about 400 ng/ml to about 2100 ng/ml,from about 450 ng/ml to about 2100 ng/ml, or from about 500 ng/ml toabout to about 2000 ng/ml within 5 minutes of administration, and, afterthe bolus dose is administered (i.e., from about 1 second to about 1hour, from about 1 second to about 45 minutes, from about 1 second toabout 30 minutes, from about 1 second to about 15 minutes, from about 1second to about 10 minutes, from about 1 second to about 5 minutes orfrom about 2 seconds to about 3 minutes after the bolus dose),administering ganaxolone via a continuous intravenous infusion over atime period from about 2 hours to about 120 hours, from about 2 hours toabout 100 hours, from about 3 hours to about 100 hours, from about 4hours to about 100 hours, or from about 4 hours to about 96 hours (e.g.,over about 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32hours, 34 hours, 36 hours, 38 hours, 40 hours, 42 hours, 44 hours, 46hours, 48 hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60hours, 62 hours, 64 hours, 66 hours, 68 hours, 70 hours, 72 hours, 74hours, 76 hours, 78 hours, 80 hours, 82 hours, 84 hours, 86 hours, 88hours, 90 hours, 92 hours, or 94 hours) in an amount and at a ratesufficient to maintain a plasma concentration of ganaxolone from about50 ng/ml to about 3500 ng/ml, from about 75 ng/ml to about 3250 ng/ml,from about 100 ng/ml to about 3000 ng/ml, from about 125 ng/ml to about2750 ng/ml, from about 150 ng/ml to about 2500 ng/ml, from about 175ng/ml to about 2250 ng/ml, from about 200 ng/ml to about 2200 ng/ml,from about 250 ng/ml to about 2150 ng/ml, from about 300 ng/ml to about2100 ng/ml, from about 350 ng/ml to about 2100 ng/ml, from about 400ng/ml to about 2100 ng/ml, from about 450 ng/ml to about 2100 ng/ml,from about 500 ng/ml to about 1800 ng/ml, from about 600 ng/ml to about1700 ng/ml, from about 650 ng/ml to about 1600 ng/ml, from about 700ng/ml to about 1500 ng/ml, from about 750 ng/ml to about 1400 ng/ml,from about 800 ng/ml to about 1300 ng/ml for from about 1 hour to about96 hours. For subjects weighing 40 kg, or more, the total daily dose ofganaxolone may be, e.g., from about 450 mg to about 2000 mg, from about500 mg to about 1900 mg, from about 500 mg to about 1800 mg, from about550 mg to about 1600 mg, from about 550 mg to about 1400 mg, from about550 mg to about 1200 mg, or from about 600 mg to about 1100 mg, and thebolus dose may comprise, e.g., from about 5 mg to about 100 mg.

The present disclosure is further directed in part to a method oftreating status epilepticus (e.g., a generalized convulsive statusepilepticus, non-convulsive status epilepticus, early statusepilepticus, established status epilepticus, refractory statusepilepticus, or super-refractory status epilepticus) comprisingadministering, a bolus dose of ganaxolone intravenously in an amountsufficient to achieve a maximum plasma ganaxolone concentration (Cmax)from about 50 ng/ml to about 3500 ng/ml, from about 75 ng/ml to about3250 ng/ml, from about 100 ng/ml to about 3000 ng/ml, from about 125ng/ml to about 2750 ng/ml, from about 150 ng/ml to about 2500 ng/ml,from about 175 ng/ml to about 2250 ng/ml, from about 200 ng/ml to about2200 ng/ml, from about 250 ng/ml to about 2150 ng/ml, from about 300ng/ml to about 2100 ng/ml, from about 350 ng/ml to about 2100 ng/ml,from about 400 ng/ml to about 2100 ng/ml, from about 450 ng/ml to about2100 ng/ml, or from about 500 ng/ml to about 1500 ng/ml within about 5minutes of administration; and, after the bolus dose (e.g., from about 1second to about 1 hour, from about 1 second to about 45 minutes, fromabout 1 second to about 30 minutes, from about 1 second to about 15minutes, from about 1 second to about 10 minutes, from about 1 second toabout 5 minutes or from about 2 seconds to about 3 minutes after thebolus dose), administering ganaxolone intravenously over a time periodfrom about 2 hours to about 120 hours, from about 2 hours to about 100hours, from about 3 hours to about 100 hours, from about 4 hours toabout 100 hours, from about 4 hours to about 96 hours, from about 5hours to about 96 hours, from about 6 hours to about 96 hours, fromabout 6 hours to about 90 hours, or from about 6 hours to about 88hours, or from about 10 hours to 72 hours via an intravenous infusion inan amount and at a rate to maintain a plasma concentration of ganaxolonefrom about 600 ng/ml to about 1500 ng/ml for more than 1 hour (e.g., forabout 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours,16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30hours, 32 hours, 34 hours, 36 hours, 38 hours, 40 hours, 42 hours, 44hours, 46 hours, 48 hours, 50 hours, 52 hours, 54 hours, 56 hours, 58hours, 60 hours, 62 hours, 64 hours, 66 hours, 68 hours, 70 hours, 72hours, 74 hours, 76 hours, 78 hours, 80 hours, 82 hours, 84 hours, 86hours, 88 hours, 90 hours, 92 hours, 94 hours, 96 hours, etc.).

The present disclosure is also directed in part to a method of treatingstatus epilepticus (e.g., a generalized convulsive status epilepticus,non-convulsive status epilepticus, early status epilepticus, establishedstatus epilepticus, refractory status epilepticus, or super-refractorystatus epilepticus) in a subject comprising administering parenterally(e.g., via an intravenous (IV) infusion) from about 400 mg to about 1500mg ganaxolone for at least one day to a subject experiencing statusepilepticus. In certain embodiments, a portion of the daily dose isadministered via a bolus injection, and the remaining portion of thedose is administered via a continuous infusion.

In addition, the disclosure is directed to a method of treating statusepilepticus (e.g., a generalized convulsive status epilepticus,non-convulsive status epilepticus, early status epilepticus, establishedstatus epilepticus, refractory status epilepticus, or super-refractorystatus epilepticus) in a subject comprising administering from about 700mg to about 1200 mg of ganaxolone intravenously, wherein theadministration provides a plasma level of ganaxolone from about 50 ng/mlto about 3500 ng/ml, from about 75 ng/ml to about 3250 ng/ml, from about100 ng/ml to about 3000 ng/ml, from about 125 ng/ml to about 2750 ng/ml,from about 150 ng/ml to about 2500 ng/ml, from about 175 ng/ml to about2250 ng/ml, from about 200 ng/ml to about 2200 ng/ml, from about 250ng/ml to about 2150 ng/ml, from about 300 ng/ml to about 2100 ng/ml,from about 350 ng/ml to about 2100 ng/ml, from about 400 ng/ml to about2100 ng/ml, from about 450 ng/ml to about 2100 ng/ml, from about 500ng/ml to about 1400 ng/ml, from about 500 ng/ml to about 1300 ng/ml,from about 500 ng/ml to about 1200 ng/ml, from about 600 ng ml to about1200 ng/ml, from about 600 ng/ml to about 1100 ng/ml, from about 650ng/ml to about 1100 ng/ml, from about 700 ng/ml to about 1100 ng/ml,from about 750 ng/ml to about 1100 ng/ml, from about 800 ng/ml to about1100 ng/ml for at least 1 hour (e.g., 2 hours, 3 hours, 4 hours, 5hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours,13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20hours, 21 hours, 22 hours, 24 hours, etc.), wherein a portion of thedose is administered via a bolus intravenous injection, and theremaining dose is administered via a continuous intravenous infusion.

This disclosure is also directed to a method of treating statusepilepticus (e.g., a generalized convulsive status epilepticus,non-convulsive status epilepticus, early status epilepticus, establishedstatus epilepticus, refractory status epilepticus, or super-refractorystatus epilepticus) in a subject comprising administering from about 500mg to about 1200 mg of ganaxolone parenterally (e.g., intravenously) fora time period from about 1 hour to 8 hours (e.g., 2, 4, 5 or 6 hours) ata variable rate from about 10 mg/hr to about 150 mg/hr, from about 15mg/hr to about 140 mg/hr, or from about 15 mg/hr to about 120 mg/hr,wherein the administration stops EEG seizure activity (e.g., continuousictal discharges) in the subject. In some embodiments, ganaxolone isadministered at a rate from about 50 mg/hr to about 130 mg/hr.

This disclosure is further directed in part to a method of treating asubject experiencing non-convulsive EEG seizures, the method comprisingadministering a therapeutically effective amount of ganaxolone to stopor reduce frequency of the non-convulsive EEG seizures in the subject.In certain embodiments, the therapeutically effective amount ofganaxolone is the amount that provides and maintains a plasmaconcentration of ganaxolone from about 50 ng/ml to about 3500 ng/ml,from about 75 ng/ml to about 3250 ng/ml, from about 100 ng/ml to about3000 ng/ml, from about 125 ng/ml to about 2750 ng/ml, from about 150ng/ml to about 2500 ng/ml, from about 175 ng/ml to about 2250 ng/ml,from about 200 ng/ml to about 2200 ng/ml, from about 250 ng/ml to about2150 ng/ml, from about 300 ng/ml to about 2100 ng/ml, from about 350ng/ml to about 2100 ng/ml, from about 400 ng/ml to about 2100 ng/ml,from about 450 ng/ml to about 2100 ng/ml, or from about 500 ng/ml toabout 1900 ng/ml in the subject. In some embodiments, a portion of thetherapeutically effective amount is administered via a bolus intravenousinjection, and the remaining portion of the therapeutically effectiveamount is administered via a continuous intravenous infusion. Forexample, when the subject weighs 40 kg, or more, in some embodiments,from about 5 mg to about 100 mg of ganaxolone is administered via thebolus intravenous injection, and the remainder of dose is administeredvia an intravenous infusion at a rate greater than 10 mg/hour, 15mg/hour, 20 mg/hour, 25 mg/hour, 30 mg/hour, 35 mg/hour, 40 mg/hour, 45mg/hour, 50 mg/hour, 55 mg/hour, 60 mg/hour, 65 mg/hour, 70 mg/hour, 75mg/hour, 80 mg/hour, or 85 mg/hour for a time period from about 1 hourto about 120 hours (e.g., 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, etc.).

This disclosure is also directed to a method of treating non-convulsiveEEG seizures comprising administering intravenously a therapeuticallyeffective dose of ganaxolone, or a portion thereof, to stop or reducefrequency of the non-convulsive EEG seizures in the subject over a timeperiod from about 2 hours to about 120 hours, from about 2 hours toabout 100 hours, from about 3 hours to about 100 hours, from about 4hours to about 100 hours, from about 4 hours to about 96 hours, fromabout 5 hours to about 96 hours, from about 6 hours to about 96 hours,from about 6 hours to about 90 hours, from about 6 hours to about 88hours, or from about 10 hours to 72 hours via a continuous intravenousinfusion, wherein the intravenous infusion is started after (e.g., fromabout 1 second to about 1 hour, from about 1 second to about 45 minutes,from about 1 second to about 30 minutes, from about 1 second to about 15minutes, from about 1 second to about 10 minutes, from about 1 second toabout 5 minutes or from about 2 seconds to about 3 minutes after thebolus dose) a bolus dose from about 5 mg to about 100 mg isintravenously administered to the subject.

This disclosure is further directed to a method of treating a subjectexperiencing non-convulsive EEG seizures comprising administeringintravenously from about 450 mg to about 3000 mg ganaxolone over a timeperiod from about 4 hours to about 120 hours at a rate greater thanabout 10 mg/hour, 15 mg/hour, 20 mg/hour, 25 mg/hour, or 30 mg/hour. Insome embodiments from about 2 mg to about 100 mg of ganaxolone isadministered via the bolus intravenous injection, and the remainder ofdose is administered via a continuous intravenous infusion at a rategreater than 10 mg/hr, 15 mg/hour, 20 mg/hr, 25 mg/hr, or 30 mg/hr for atime period from about 1 hour to about 120 hours.

This disclosure is also directed to a method of treating statusepilepticus (e.g., a generalized convulsive status epilepticus,non-convulsive status epilepticus, early status epilepticus, establishedstatus epilepticus, refractory status epilepticus, or super-refractorystatus epilepticus), comprising administering from about 450 mg to about1000 mg of ganaxolone intravenously to a subject in need thereof forabout 24 hours to about 120 hours, and administering a dose of anadditional antiepileptic drug during said 24 hours to about 120 hours.The additional antiepileptic drug may be selected from the groupconsisting benzodiazepines, phenytoin, fosphenytoin, valproic acid,phenobarbital, and/or levetiracetam. In certain embodiments, theantiepileptic drug is a benzodiazepine (e.g., diazepam, lorazepam,etc.). In some of these embodiments, administration of ganaxolone andthe additional antiepileptic drug provides a synergistic effect.

This disclosure is also directed to a method of treating AcuteRepetitive Seizures (ARS) comprising administering a therapeuticallyeffective amount of ganaxolone intravenously to a subject in needthereof. The therapeutically effective amount may comprise, e.g., fromabout 1 mg to about 1000 mg of ganaxolone and may be administered as oneor more bolus doses, each bolus dose comprising from about 1 mg to about50 mg, from about 1 mg to about 45 mg, from about 1 mg to about 40 mg,from about 2 mg to about 35 mg, from about 3 mg to about 30 mg, or fromabout 5 mg to about 30 mg and administered over about 1 to about 5minutes. In some embodiments, the method further comprisesadministering, after the one or more bolus doses of ganaxolone, acontinuous intravenous infusion of ganaxolone at a rate between about 5mg/hour and about 130 mg/hour (e.g., from about 5 mg/hour to about 85mg/hour) for about 24 hours to about 120 hours (e.g., for about 48 hoursto about 96 hours), the continuous intravenous infusion started at aboutthe time of the bolus injection or a short time thereafter (e.g., withinabout 30 min); and lowering the rate of intravenous infusion rate overabout 10 hours to about 24 hours (e.g., over 10 hours, about 12 hours,about 14 hours, about 16 hours, about 18 hours, or about 20 hours)before the continuous infusion is stopped.

In certain embodiments, the methods of the invention further compriseadministering one or more rescue bolus dose(s) of ganaxolone from about1 mg to about 50 mg, from about 1 mg to about 45 mg, from about 1 mg toabout 40 mg, from about 2 mg to about 35 mg, from about 3 mg to about 30mg, or from about 5 mg to about 30 mg may be administered intravenouslyover about 1 to about 5 minutes during the intravenous infusion. The oneor more rescue dose(s) may be administered, e.g., in the event there isseizure(s) (i.e., abnormal EEG activity) and/or convulsion(s) relapse.In some embodiments, one, two, three, four or five rescue doses areadministered during the intravenous infusion.

In certain embodiments, the methods of the invention compriseadministering some or all of the doses of ganaxolone in the form ofnanoparticles.

3. BRIEF DESCRIPTION OF THE DRAWINGS

The drawings are not necessarily to scale or exhaustive. Instead, theemphasis is generally placed upon illustrating the principles of theinventions described herein. The accompanying drawings, which constitutea part of the specification, illustrate several embodiments consistentwith the disclosure and, together with the description, serve to explainthe principles of the disclosure. In the drawings:

FIG. 1 depicts EEG and BIS changes of the Phase 1 clinical study ofExample 1. The changes are consistent with sedative/anesthetic effectsof ganaxolone.

FIG. 2 is a graph showing predicted ganaxolone plasma concentrationagainst time.

FIG. 3 is a graph showing predicted and actual ganaxolone plasmaconcentration against time for subject 004-101. The vertical line marksthe time of seizure relapse.

FIG. 4 is a snapshot of electroencephalography for subject 004-101.

FIG. 5 is a graph showing predicted and actual ganaxolone plasmaconcentration against time for subject 004-102. The vertical line marksthe beginning of the return of abnormal EEG activity that later requiredadditional intervention.

FIG. 6 is a snapshot electroencephalography for subject 004-102.

FIG. 7 is a graph showing predicted and actual ganaxolone plasmaconcentration against time for subject 006-101. The vertical line marksthe time of seizure relapse.

FIG. 8 is a photograph of electroencephalography for subject 106-102.The vertical line marks the time of ganaxolone treatment initiation.

FIG. 9 is a graph showing predicted and actual ganaxolone plasmaconcentration against time for subject 006-102. The vertical line marksthe time of seizure relapse.

FIG. 10 is a graph showing predicted and actual ganaxolone plasmaconcentration against time for subject 015-101.

FIG. 11 is a snapshot of electroencephalography of Subject from eIND No.131,642. Seizures appear as dark areas, as indicated by the comments onthe upper margin.

FIG. 12 is a graph showing the time to SE cessation in low, medium, andhigh dose groups. The graph shows that the median for SE cessation inall dose groups was 5 minutes.

FIG. 13A is a graph showing the PK/PD relationship and rationale for thetarget dose. FIGS. 13B-13D are exemplary electroencephalograms (EEG)showing that acute maintenance of ganaxolone plasma concentrations ≥500ng/mL resulted in improved seizure control on EEG.

FIG. 14 is a graph depicting modeled PK curves for low, medium, and highdosing cohorts.

FIG. 15 is a graph depicting percent change in EEG seizure burden inrefractory SE patients administered IV ganaxolone in low, medium, andhigh dosing cohorts.

4. DETAILED DESCRIPTION

Effectively treating SE has been challenging, and conventional treatmentprotocols are not effective for many patients. About 50% of subjectsfail to respond to treatment with first-line agents, and about 50% ofsuch subjects also fail to respond to treatment with second-line agents,thus progressing to refractory SE. Approximately one third of refractorysubjects die and another third recover, but with neurological or otherdeficits. There is clearly a need for improved methods for treating SE.

The disclosure relates to a new method for treating SE. As exemplifiedand described herein, treatment according to the method provides rapidSE suppression, and also provides for continued suppression of SE. Themethod can be used to treat any form of SE, including generalizedconvulsive SE, non-convulsive SE, refractory SE, and super refractorySE. The method is particularly useful for treating refractory SE. Themethod can also be used to treat subjects that have failed first-linetreatment, second-line treatment, and/or third-line treatment.

SE presents as a prolong seizure for a period of at least 5 minutes orlonger or seizures without recovery consciousness between seizures.Suppression of SE typically breaks the seizures (i.e., suppresses orreduces seizure activity). Clinically, suppression of SE can bereduction in seizure burden (i.e., the percent of time during whichthere is electrographic seizure activity). For instance, a clinician mayconsider a seizure burden less than 20% suppression of SE and/or aseizure burden that is at least 50% less than during the 30 minutesprior to the initiation of treatment (i.e., intravenous bolus pluscontinuous intravenous infusion).

The method described herein comprises administering to a subject atherapeutically effective amount of a neurosteroid (e.g., ganaxolone) asan intravenous bolus and a continuous intravenous infusion. Theintravenous bolus of ganaxolone is administered in an amount that issufficient to suppress SE. Typically, a neurosteroid (e.g. ganaxolone)plasma concentration of about 500 ng/ml to about 1000 ng/ml issufficient to suppress SE. For example, to achieve a ganaxolone plasmaconcentration of about 500 ng/ml to about 1000 ng/ml, about 30 mg bolusof ganaxolone can be administered. Treatment according to the methodlasts for a treatment period, which includes a period during which thecontinuous intravenous infusion is administered to maintain thesubject's serum concentration of neurosteroid (e.g., ganaxolone) at orabout a target level (i.e., a target concentration period), and periodsduring which the subjects plasma concentration of neurosteroid (e.g.,ganaxolone) is allowed to or caused to fall below the targetconcentration, and a taper period during which the patient is weaned offthe neurosteroid.

The continuous intravenous infusion of neurosteroid (e.g. ganaxolone) isadministered for a target concentration period in an amount sufficientfor continued suppression of SE. Continued suppression of SE is achievedwhen the continuous infusion maintains a plasma concentration ofneurosteroid (e.g. ganaxolone) of about 500 ng/ml or higher throughoutthe target concentration period. The target concentration period istypically at least about 8 hours or at least about 12 hours, although itis possible that the target concentration period can be at least about 4hours in some subjects. During the target concentration period, theamount of neurosteroid (e.g. ganaxolone) administered to the subject(i.e., by the continuous intravenous infusion) can be increased ordecreased to maintain continued suppression of SE, but is sufficient tomaintain a plasma concentration of ganaxolone in the subject of at leastabout 500 ng/ml for at least 4 hours, or preferably about 8 hoursfollowing the administration of the intravenous bolus and, optionallythroughout the treatment period. Typically, the amount of ganaxoloneadministered by the continuous intravenous infusion is decreased over aperiod of about 24 hours from the initiation of the intravenousinfusion. For instance, the amount of ganaxolone administered to thesubject can be decreased about 2 hours after the initiation of thecontinuous intravenous infusion, and then about 10 hours to about 14hours after infusion. Surprisingly, SE continues to be suppressed by thecontinuous intravenous infusion even though the amount of neurosteroid(e.g. ganaxolone) administered during the continuous intravenousinfusion is decreased during the treatment period. As a result, themethod provide enhanced safety and efficacy with lower exposure toganaxolone than was expected. During treatment the subject can bemonitored for plasma concentration of neurosteroid (e.g. ganaxolone) andusing EEG for seizure activity. If the subject appears to show signs ofSE re-lapse, the amount of ganaxolone administered can be adjustedaccordingly. For instance, an additional intravenous bolus can beprovided or the amount of ganaxolone infused can be increased. Theamount of neurosteroid (e.g. ganaxolone) administered during infusion istypically adjusted by increasing or decreasing the infusion rate.

The continuous intravenous infusion is generally administeredconcurrently with the administration of the intravenous bolus. Although,in some cases, the continuous intravenous infusion can be initiatedbefore or after the intravenous bolus.

The continuous intravenous infusion is typically followed by a taperperiod during which the subject is weaned off ganaxolone. During thetaper period the continuous intravenous infusion of ganaxolone issystematically decreased, typically by reducing the amount of ganaxolonethat is administered to the subject (e.g., by the continuous intravenousinfusion) by about one third every four hours until the subject nolonger requires ganaxolone.

Additional description of the method and guidance for the practice ofthe method are provided herein. For ease of presentation, furtherdetails and guidance are provided with respect to a preferred aspectusing ganaxolone. It is intended that the further details and guidancealso relate to treatment with other neurosteroids.

a. Intravenous Bolus

The method for treating SE comprises administering to a subject in needthereof an intravenous bolus of ganaxolone in an amount sufficient tosuppress SE, which typically is an amount sufficient to produce aganaxolone plasma concentration of at least about 500 ng/ml to about1000 ng/ml. Typically the intravenous bolus results in a ganaxoloneplasma concentration of about 750 ng/ml to about 1000 ng/ml, and moretypically about 1000 ng/ml.

For example, the intravenous bolus of ganaxolone can include an amountof ganaxolone that is sufficient to achieve a ganaxolone plasmaconcentration of at least about 500 ng/ml, about 525 ng/ml, about 550ng/ml, about 575 ng/ml, about 600 ng/ml, about 625 ng/ml, about 650ng/ml, about 675 ng/ml, about 700 ng/ml, about 725 ng/ml, about 750ng/ml, about 775 ng/ml, about 800 ng/ml, about 825 ng/ml, about 850ng/ml, about 875 ng/ml, about 900 ng/ml, about 925 ng/ml, about 950ng/ml, about 975 ng/ml, about 1000 ng/ml, about 1025 ng/ml, about 1050ng/ml, about 1075 ng/ml, or about 1100 ng/ml. Preferably, theintravenous bolus achieves a ganaxolone plasma concentration of at leastabout 500 ng/ml to about 1000 ng/ml.

While a ganaxolone plasma concentration of at least about 500 ng/ml toabout 1000 ng/ml is preferable to suppress SE, there can be somevariability based on, for example a differences in subjects' weight,metabolism, age, duration of SE and/or severity of SE. Accordingly, askilled clinician will understand that lower exposure to ganaxolone,such as a plasma concentration of at least about 425 ng/ml, at leastabout 450 ng/ml, at least about 475 ng/ml, could suppress SE in some SEpatients. However, it is preferred that the bolus delivers an amount ofganaxolone that is sufficient to achieve a plasma concentration ofganaxolone of about 1000 ng/ml. A plasma concentration of ganaxoloneabove about 1000 ng/ml can induce anesthesia in a subject, which isgenerally not an intended effect or desired outcome of the methodsdescribed herein. Preferably, the intravenous bolus of ganaxoloneresults in minimal or no anesthetic effects. For example, preferably,the amount of ganaxolone administered does not result in loss ofconsciousness, does not result in paralysis, and/or does not cause deepsedation. Preferably, treatment in accordance with the methods describedherein does not require the subject to undergo controlled ventilationand/or endotracheal intubation.

In some instances, a plasma concentration of about 1005 ng/ml, about1010 ng/ml, 1020 ng/ml, 1030 ng/ml, 1040 ng/ml, 1050 ng/ml, 1060 ng/ml,1070 ng/ml, 1080 ng/ml, can be achieved to suppress SE without resultingin anesthesia. In other instances, a ganaxolone plasma concentrationthat is greater than 1000 ng/ml by about 1%, about 2%, about 3%, about4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about11%, about 12%, about 13%, about 14%, or about 15% can be sufficient tosuppress SE without resulting in anesthesia.

The intravenous bolus of ganaxolone can be administered (i.e., infused)into the subject at an amount of about 1 mg, about 2 mg, about 3 mg,about 4 mg/hr, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg/, about 14 mg,about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg,about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg,about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 45 mg, about50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.Preferably, about 30 mg of ganaxolone is infused into the subject duringthe intravenous bolus.

In subjects weighing less than about 40 kg, about 0.10 mg/kg, about 0.11mg/kg, about 0.12 mg/kg, about 0.13 mg/kg, about 0.14 mg/kg, about 0.15mg/kg, about 0.16 mg/kg, about 0.17 mg/kg, about 0.18 mg/kg, about 0.19mg/kg, about 0.20 mg/kg, about 0.21 mg/kg, about 0.22 mg/kg, about 0.23mg/kg, about 0.24 mg/kg, about 0.25 mg/kg, about 0.26 mg/kg, about 0.27mg/kg, about 0.28 mg/kg, about 0.29 mg/kg, about 0.30 mg/kg, about 0.31mg/kg, about 0.32 mg/kg, about 0.33 mg/kg, about 0.34 mg/kg, about 0.35mg/kg, about 0.36 mg/kg, about 0.37 mg/kg, about 0.38 mg/kg, about 0.39mg/kg, about 0.40 mg/kg, about 0.41 mg/kg, about 0.42 mg/kg, about 0.43mg/kg, about 0.44 mg/kg, about 0.45 mg/kg, about 0.46 mg/kg, about 0.47mg/kg, about 0.48 mg/kg, about 0.49 mg/kg, about 0.5 mg/kg, about 0.51mg/kg, about 0.52 mg/kg, about 0.53 mg/kg, about 0.54 mg/kg, about 0.55mg/kg, about 0.56 mg/kg, about 0.57 mg/kg, about 0.58 mg/kg, about 0.59mg/kg, about 0.60 mg/kg, about 0.61 mg/kg, about 0.62 mg/kg, about 0.63mg/kg, about 0.64 mg/kg, about 0.65 mg/kg, about 0.66 mg/kg, about 0.67mg/kg, about 0.68 mg/kg, about 0.69 mg/kg, about 0.7 mg/kg, about 0.75mg/kg, about 0.80 mg/kg, about 0.85 mg/kg, about 0.90 mg/kg, about 0.95mg/kg of ganaxolone can be infused into the subject during theintravenous bolus. Preferably, about 0.43 mg/kg of ganaxolone is infusedinto the subject during the intravenous bolus.

The intravenous bolus can be administered to the subject for any desiredperiod of time and is typically administered from about 1 minute toabout 10 minutes, such as, from about 1 minute to about 5 minutes, about1 minute to about 4 minutes, about 1 minute to about 3 minutes, about 1minute to about 2 minutes, about 2 minutes to about 5 minutes, about 2minutes to about 4 minutes, about 2 minutes to about 3 minutes, about 3minutes to about 5 minutes, or about 3 minutes to about 4 minutes. Theintravenous bolus can preferably be administered to the subject forabout 1 minute, about 2 minutes, about 3 minutes, or about 5 minutes.More preferably, the intravenous bolus is administered to the subjectfor about 3 minutes.

In instances when a ganaxolone plasma concentration of at least about500 ng/ml is not achieved after the intravenous bolus of ganaxolone, thesubject may be administered an additional intravenous bolus ofganaxolone to achieve a ganaxolone plasma concentration of at leastabout 500 ng/ml, and preferably about 1000 ng/ml.

b. Continuous Intravenous Infusion

The continuous intravenous infusion of ganaxolone is administeredperiprocedural with the intravenous bolus. For instance, the continuousintravenous infusion can be initiated concurrently with theadministration of the intravenous bolus. Alternatively, the continuousintravenous infusion can be initiated before or after the administrationof the intravenous bolus. Typically, the intravenous infusion andcontinuous intravenous infusion is administered from the same ganaxolonesource (e.g., and intravenous bag connect to IV line) and are initiatedconcurrently. The continuous intravenous infusion of ganaxolone isadministered in an amount to continue SE suppression throughout thetreatment period and beyond. The continuous intravenous infusion ofganaxolone provides durable suppression of SE that lasts preferablythrough the treatment period, preferably through the taper period,preferably after the taper period, and preferably post-treatment.

In embodiments, the continuous intravenous infusion of ganaxoloneachieves suppression of SE for at least 1 hour, at least 2 hours, atleast 3 hours, at least 4 hours, at least 5 hours, at least 6 hours atleast 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, atleast 11 hours, at least 12 hours, at least 1 day, at least 2 days, atleast 3 days, at least 4 days, at least 5 days, at least 6 days, atleast 7 days or longer post-treatment. In embodiments, the continuousintravenous infusion of ganaxolone achieves suppression of SE for atleast 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, atleast 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, atleast 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeksor longer post-treatment. In embodiments, the continuous intravenousinfusion of ganaxolone achieves suppression of SE for at least 1 month,at least 2 months, at least 3 months, at least 4 months, at least 5months, at least 6 months, at least 7 months, at least 8 months, atleast 9 months, at least 10 months, at least 11 months, at least 12months or longer post-treatment.

Continued SE suppression is achieved by administering to the subject acontinuous intravenous infusion in an amount sufficient to produce aganaxolone plasma concentration of at least about 500 ng/ml for a targetconcentration period, which typically is at least about 4 hours, orpreferably at least about 8 hours or at least about 12 hours followingthe administration of the intravenous bolus, and optionally throughoutthe treatment period. In practice, the patient's plasma concentration ofganaxolone can be monitored and the amount of ganaxolone that is infusedcan be adjusted or titrated to maintain a plasma concentration of atleast about 500 ng/ml throughout the treatment period. A ganaxoloneplasma concentration of at least about 500 ng/ml period, for example forabout 4 hours, about 5 hours about 6 hours, about 7 hours, about 8hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours orlonger can achieve continued SE suppression.

The continuous intravenous infusion of ganaxolone can be administered tothe subject in an amount to achieve a ganaxolone plasma concentration ofabout 500 ng/ml to about 1000 ng/ml for at least 4 hours, and preferablyat least about 8 hours or at least about 12 hours.

While a plasma concentration of at least about 500 ng/ml is preferablefor continued SE suppression, there can be some variability based on,for example, differences in subjects' weight, metabolism, age, durationof SE and/or severity of SE. Accordingly, a skilled clinician willunderstand that, for example, a ganaxolone plasma concentration of atleast about 425 ng/ml, at least about 450 ng/ml, at least about 475ng/ml can be sufficient for continued SE suppression in some SEsubjects. A ganaxolone plasma concentration less than 400 ng/ml or lessthan 500 ng/mL will typically not be sufficient for continued SEsuppression. In embodiments, the continuous intravenous infusion ofganaxolone achieves a ganaxolone plasma concentration of about 425ng/ml, about 450 ng/ml, about 475 ng/ml, about 500 ng/ml, about 525ng/ml, about 550 ng/ml, about 575 ng/ml, about 600 ng/ml, about 625ng/ml, about 650 ng/ml, about 675 ng/ml, about 700 ng/ml, about 725ng/ml, about 750 ng/ml, about 775 ng/ml, about 800 ng/ml, about 825ng/ml, about 850 ng/ml, about 875 ng/ml, about 900 ng/ml, about 925ng/ml, about 950 ng/ml, about 975 ng/ml, about 1000 ng/ml, about 1025ng/ml, about 1050 ng/ml, about 1075 ng/ml, or about 1100 ng/ml.Preferably, a ganaxolone plasma concentration of about 500 ng/ml toabout 1000 ng/ml is desired.

A plasma concentration of ganaxolone above about 1000 ng/ml can induceanesthesia in a subject, which is generally not an intended effect ordesired outcome of the methods described herein. Preferably, thecontinuous intravenous infusion of ganaxolone results in minimal or noanesthetic effects. For example, preferably, the amount of ganaxoloneadministered does not result in loss of consciousness, does not resultin paralysis, and/or does not cause deep sedation. Preferably, treatmentin accordance with the methods described herein does not require thesubject to undergo controlled ventilation and/or endotrachealintubation.

In some instances, a ganaxolone plasma concentration of about 1005ng/ml, about 1010 ng/ml, 1020 ng/ml, 1030 ng/ml, 1040 ng/ml, 1050 ng/ml,1060 ng/ml, 1070 ng/ml, 1080 ng/ml, can result in continued SEsuppression without causing anesthesia. In instances, a ganaxoloneplasma concentration less than about 1%, less than about 2%, less thanabout 3%, less than about 4%, less than about 5%, less than about 6%,less than about 7%, less than about 8%, less than about 9%, less thanabout 10%, less than about 11%, less than about 12%, less than about13%, less than about 14%, or less than about 15% of 500 ng/ml can besufficient to suppress SE. In other instances, a ganaxolone plasmaconcentration greater about 1%, than about 2%, bout 3%, about 4%, about5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about12%, about 13%, about 14%, or about 15% of 1000 ng/ml can be sufficientfor continued SE suppression without resulting in anesthesia.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased over the continuousintravenous infusion treatment period. In instances, the continuousintravenous infusion can be decreased over a period of about 24 hoursfrom the initiation of the intravenous infusion. For example, the amountof ganaxolone administered to the subject per hour by continuousintravenous infusion can be decreased about 1 hour, about 1.5 hours,about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4hours, about 4.5 hours, about 5 hours, about 6 hours, about 7 hours,about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours,about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22hours, about 23 hours, or about 24 hours after the initiation of thecontinuous intravenous infusion.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased or further decreased atone or more periods over the continuous intravenous infusion treatmentperiod. For example, the amount of ganaxolone administered to thesubject per hour by continuous intravenous infusion can be decreased atone interval, two intervals, three intervals, four intervals, fiveintervals or more during the continuous intravenous infusion treatmentperiod. In the methods provided herein, the amount of ganaxoloneadministered to the subject per hour by continuous intravenous infusionis preferably decreased at two time intervals over about 24 hours fromthe initiation of the continuous intravenous infusion.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be deceased or further decreasedbetween about 1 hours to about 5 hours, about 1 hour to about 4 hours,about 1 hour to about 3 hours, about 2 hours to about 3 hours, about 2hours to about 4 hours, about 2 hours to about 4 hours, about 2 hours toabout 5 hours, about 3 hours to about 4 hours, about 4 hours to about 5hours after the initiation of the continuous intravenous infusion. Theamount of ganaxolone administered to the subject per hour by continuousintravenous infusion is preferably decreased about 2 hours after theinitiation of the continuous intravenous infusion.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased or further decreasedabout 8 hours to about 16 hours, about 8 hours to about 15 hours, about8 hours to about 14 hours, about 8 hours to about 13 hours, about 8hours to about 12 hours, about 8 hours to about 11 hours, about 8 hoursto about 10 hours, about 9 hours to about 16 hours, about 9 hours toabout 15 hours, about 9 hours to about 14 hours, about 9 hours to about13 hours, about 9 hours to about 12 hours, about 9 hours to about 11hours, about 9 hours to about 10 hours, about 10 hours to 16 hours,about 10 hours to about 15 hours, about 10 hours to about 14 hours,about 10 hours to about 13 hours, about 10 hours to about 12 hours,about 10 hours to about 11 hours after the initiation of the continuousintravenous infusion. The amount of ganaxolone administered to thesubject per hour by continuous intravenous infusion is preferablydecreased at about 10 hours to about 14 hours after the initiation ofthe continuous intravenous infusion. More specifically, the amount ofganaxolone administered to the subject per hour by continuousintravenous infusion is decreased at about 12 hours after the initiationof the continuous intravenous infusion.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased between about 1 hoursto about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3hours, about 2 hours to about 3 hours, about 2 hours to about 4 hours,about 2 hours to about 4 hours, about 2 hours to about 5 hours, about 3hours to about 4 hours, about 4 hours to about 5 hours after theinitiation of the continuous intravenous infusion, and then about 8hours to about 16 hours, about 8 hours to about 15 hours, about 8 hoursto about 14 hours, about 8 hours to about 13 hours, about 8 hours toabout 12 hours, about 8 hours to about 11 hours, about 8 hours to about10 hours, about 9 hours to about 16 hours, about 9 hours to about 15hours, about 9 hours to about 14 hours, about 9 hours to about 13 hours,about 9 hours to about 12 hours, about 9 hours to about 11 hours, about9 hours to about 10 hours, about 10 hours to 16 hours, about 10 hours toabout 15 hours, about 10 hours to about 14 hours, about 10 hours toabout 13 hours, about 10 hours to about 12 hours, about 10 hours toabout 11 hours after the initiation of the continuous intravenousinfusion.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion is preferably decreased at about 2 hoursafter the initiation of the continuous intravenous infusion, and thenabout 10 hours to about 14 hours after the initiation of the continuousintravenous infusion.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased by about 40%, about45%, about 50%, about 55%, about 65%, about 75%, about 80%, about 85%,or about 90% relative to the amount administered per hour at theinitiation of the continuous intravenous infusion.

In embodiments, the amount of ganaxolone administered to the subject perhour by continuous intravenous infusion can be decreased by about 40%,about 45%, about 50%, about 55%, about 65%, about 75%, about 80%, about85%, or about 90%, relative to the amount administered per hour at theinitiation of the continuous intravenous infusion, about 1 hour, about1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5hours, about 4 hours, about 4.5 hours, about 5 hours, about 6 hours,about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11hours, about 12 hours, about 14 hours, about 15 hours, about 16 hours,about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21hours, about 22 hours, about 23 hours, or about 24 hours after theinitiation of the continuous intravenous infusion.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased by about 40%, about45%, about 50%, about 55%, or about 60% relative to the amountadministered per hour at the initiation of the continuous intravenousinfusion, about 1 hour to about 5 hours after the initiation of thecontinuous intravenous infusion. The amount of ganaxolone administeredto the subject per hour by continuous intravenous is preferablydecreased by about 50%, relative to the amount administered per hour atthe initiation of the continuous intravenous infusion, about 2 hoursafter the initiation of the continuous intravenous infusion.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased by about 50%, about55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85%relative to the amount administered per hour at the initiation of thecontinuous intravenous infusion, about 10 hours to about 14 hours afterthe initiation of the continuous intravenous infusion. The amount ofganaxolone administered to the subject per hour by continuousintravenous infusion is preferably decreased by about 75%, relative tothe amount administered per hour at the initiation of the continuousintravenous infusion, about 10 hours after the initiation of thecontinuous intravenous infusion.

The continuous intravenous infusion comprises infusing into the subjectabout 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 65 mg,about 70 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, orabout 100 mg of ganaxolone per hour during the continuous intravenousinfusion. Preferably, the continuous intravenous infusion comprisesinfusing into the subject about 20 mg of ganaxolone per hour to about 80mg of ganaxolone per hour during the continuous infusion treatmentperiod.

In embodiments, about 70 mg, about 71 mg, about 72 mg, about 73 mg,about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg,about 85 mg, about 86 mg, about 87 mg, or about 89 mg, about 90 mg ofganaxolone are infused into the subject at the initiation of thecontinuous intravenous infusion. About 80 mg of ganaxolone per hour ispreferably infused into the subject at the initiation of the continuousintravenous infusion. The amount of ganaxolone can then be decreased toabout 60 mg, about 55 mg, about 40 mg, about 35 mg, about 30 mg, about25 mg, about 20 mg, about 15 mg, or about 10 mg. Preferably the amountof ganaxolone is decreased to about 40 mg of ganaxolone and then about20 mg of ganaxolone during the treatment period.

In embodiments, about 40 mg of ganaxolone per hour is administered tothe subject by continuous intravenous infusion starting about 2 hoursafter initiation of the continuous intravenous infusion and for about 6hours to about 10 hours thereafter. In embodiments, about 20 mg ofganaxolone per hour is administered to the subject by continuousintravenous infusion starting about 12 hours after initiation of thecontinuous intravenous infusion and for about 12 hours to about 24 hoursthereafter. If desired or medically indicated, the amount of ganaxoloneinfused into the subject by continuous intravenous infusion can beincreased up to about 45 mg of ganaxolone per hour starting about 24hours after initiation and for up to about 12 hours thereafter. Ingeneral, the amount of ganaxolone administered to the subject bycontinuous intravenous infusion does not exceed 45 mg ganaxolone perhour.

The amount of ganaxolone administered to the subject per hour bycontinuous intravenous infusion can be decreased or increased byincreasing or decreasing the rate of infusion. The rate of infusion willgenerally vary between about 5 mg/hour of ganaxolone to about 130mg/hour of ganaxolone, depending on clinical response and safety. Incertain embodiments, the rate of administration is from about 5 mg/hourto about 90 mg/hour.

The treatment period of the continuous intravenous infusion can be for aperiod of at least 4 hours, at least 5 hours, at least 6 hours, at least7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least11 hours, at least 12 hours, at least 13 hours, at least 14 hours, atleast 15 hours, at least 16 hours, at least 17 hours, at least 18 hours,at least 19 hours, at least 20 hours, at least 21 hours, at least 22hours, at least 23 hours, at least 24 hours, at least 25 hours, at least26 hours, at least 27 hours, at least 28 hours, at least 29 hours, atleast 30 hours, at least 31 hours, at least 32 hours, at least 33 hours,at least 34 hours, at least 35 hours, at least 36 hours, at least 37hours, at least 38 hours, at least 39 hours, at least 40 hours after theinitiation of the continuous intravenous infusion. A preferredcontinuous intravenous infusion period is for a period of about 8 hoursto about 36 hours after the initiation of the continuous intravenousinfusion. Generally, the continuous intravenous infusion is a period ofabout 36 hours but can be longer, such as for about 48 hours, about 72hours, or about 96 hours.

During continuous intravenous infusion of ganaxolone, one or moreadditional intravenous bolus of ganaxolone can be administered to asubject that shows signs of SE re-lapse or experiences SE re-lapse.Electroencephalogram (EEG) can be used to detect signs of SE re-lapse.Plasma concentration of ganaxolone can alternatively or in combinationwith EEG be used to detect signs of SE re-lapse or a subject thatexperiences SE re-lapse. For example, a ganaxolone plasma concentrationbelow 400 ng/ml can suggest that the subject is likely to re-lapse.

One or more additional intravenous bolus of ganaxolone from about 1 mgto about 100 mg, from about 1 mg to about 90 mg, about 1 mg to about 80mg, about 2 mg to about 75 mg, from about 3 mg to about 70 mg, fromabout 5 mg to about 60 mg, from about 5 mg to about 50 mg, from about 5mg to about 45 mg, or from about 5 mg to about 35 mg may be administeredintravenously over about 1 to about 5 minutes, e.g., in the event thereis seizure(s) (i.e., abnormal EEG activity) and/or convulsion(s)relapse.

The additional intravenous bolus of ganaxolone can be infused into thesubject at an amount of about 1 mg/hr, about 2 mg/hr, about 3 mg/hr,about 4 mg/hr, about 5 mg/hr, about 6 mg/hr, about 7 mg/hr, about 8mg/hr, about 9 mg/hr, about 10 mg/hr, about 11 mg/hr, about 12 mg/hr,about 13 mg/hr, about 14 mg/hr, about 15 mg/hr, about 16 mg/hr, about 17mg/hr, about 18 mg/hr, about 19 mg/hr, about 20 mg/hr, about 21 mg/hr,about 22 mg/hr, about 23 mg/hr, about 24 mg/hr, about 25 mg/hr, about 26mg/hr, about 27 mg/hr, about 28 mg/hr, about 29 mg/hr, about 30 mg/hr,about 31 mg/hr, about 32 mg/hr, about 33 mg/hr, about 34 mg/hr, about 35mg/hr, about 36 mg/hr, about 37 mg/hr, about 38 mg/hr, about 39 mg/hr,about 40 mg/hr, about 45 mg/hr, about 50 mg/hr, about 55 mg/hr, about 60mg/hr, about 65 mg/hr, about 70 mg/hr, about 75 mg/hr, about 80 mg/hr,about 85 mg/hr, about 90 mg/hr, about 95 mg/hr, or about 100 mg/hr ofganaxolone per hour prior to seizure re-lapse or upon detection ofseizure re-lapse over a period of about 1 minute to about 5 minutes.

c. Taper Period

The method for treating SE can further comprise continuing to administerto a subject in need thereof the continuous intravenous infusion for ataper period. The taper period follows the target concentration period.Generally, the taper period immediately follows the continuousintravenous infusion treatment period. Although, in some cases, thetaper period can immediately follow the target concentration period.When the continuous intravenous has a treatment period of about 36 hoursor longer (i.e., 8 hours, about 72 hours, or about 96 hours), the taperperiod starts immediately after the treatment period.

During the taper period the amount of ganaxolone administered to thesubject per hour is reduced by about 5%, about 10%, about 15%, about20%, about 25%, about 30%, about 35%, about 40%, about 50% or more aboutevery 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about10 hours, about 11 hours, or about 12 hours until the subject is weanedoff ganaxolone.

During the taper period the amount of ganaxolone administered to thesubject per hour is reduced by about one third about every 1 hour, about2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours,about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11hours, or about 12 hours. Preferably, during the taper period the amountof ganaxolone administered to the subject per hour is reduced by aboutone third about every four hours.

The taper period can be for a period of at least about 1 hour, at leastabout 2 hours, at least about 3 hours, at least about 4 hours, at leastabout 5 hours, at least about 6 hours, at least about 7 hours, at leastabout 8 hours, at least about 9 hours, at least about 10 hours, at leastabout 11 hours, at least about 12 hours, at least about 13 hours, atleast about 14 hours, at least about 15 hours, at least about 16 hours,at least about 17 hours, at least about 18 hours, at least about 19hours, at least about 20 hours, at least about 21 hours, at least about22 hours, at least about 23 hours, at least about 24 hours, at leastabout 25 hours, at least about 26 hours, at least about 27 hours, atleast about 28 hours, at least about 29 hours, at least about 30 hours,at least about 32 hours, at least about 36 hours, at least about 48hours, at least about 72 hours, at least about 96 hours, or longer untilthe subject is weaned off ganaxolone.

As an alternative, the continuous intravenous infusion can be stopped,and oral ganaxolone can be administered to the subject. Oral ganaxolonecan be used in place of the taper period to maintain a ganaxolone serumconcentration of about 200 ng/ml to about 400 ng/ml.

In certain embodiments, the methods disclosed herein further comprise,after stopping the continuous intravenous infusion of ganaxolone, orallyadministering ganaxolone to the subject. The oral daily dose ofganaxolone may be, e.g., from about 200 mg to about 3000 mg, from about400 mg to about 2000 mg, from about 600 mg to about 1900 mg, or fromabout 900 mg to about 1800 mg, and may be administered in an oralcapsule, oral suspension or an oral tablet. In certain embodiments, theoral daily dose of ganaxolone may be, e.g., from about 200 mg to about2000 mg, from about 400 mg to about 1500 mg, from about 400 mg to about1250 mg, or from about 400 mg to about 1000 mg, and may be administeredin an oral capsule, oral suspension or an oral tablet. The oraladministration may continue, e.g., for about 7 days, 14 days, 21 days,28 days or longer.

In certain embodiments, one or more oral doses of ganaxolone areadministered before or after the continuous intravenous infusion orintravenous doses of ganaxolone. The oral daily dose of ganaxolone maybe, e.g., from about 200 mg to about 3000 mg, from about 400 mg to about2000 mg, from about 600 mg to about 1900 mg, or from about 900 mg toabout 1800 mg, and may be administered in an oral capsule, oralsuspension or an oral tablet. In certain embodiments, the oral dailydose of ganaxolone may be, e.g., from about 200 mg to about 2000 mg,from about 400 mg to about 1500 mg, from about 400 mg to about 1250 mg,or from about 400 mg to about 1000 mg, and may be administered in anoral capsule, oral suspension or an oral tablet. The oral administrationmay continue, e.g., for about 7 days, 14 days, 21 days, 28 days orlonger.

The methods of the present invention encompass, e.g., administration ofone or more intravenous bolus of ganaxolone, followed by administrationganaxolone via an continuous intravenous infusion; administration of oneor more intravenous bolus of ganaxolone, followed by administrationganaxolone via a continuous intravenous infusion; and followed byadministration of ganaxolone orally, e.g., in an oral capsule, an oraltablet, an oral suspension, or an oral solution; administration ofganaxolone orally, e.g., in an oral capsule, an oral tablet, an oralsuspension or an oral solution, followed by administration of ganaxolonevia a continuous intravenous infusion; administration of ganaxoloneorally, e.g., in an oral capsule, an oral tablet, an oral suspension oran oral solution, followed by administration of ganaxolone via acontinuous intravenous infusion, wherein one or more intravenous bolusof ganaxolone is administered during the intravenous infusion;administration of ganaxolone orally, e.g., in an oral capsule, an oraltablet, an oral suspension or an oral solution, followed byadministration of ganaxolone via one or more intravenous bolus ofganaxolone, and followed by administration of ganaxolone via acontinuous intravenous infusion; administration of ganaxolone orally,e.g., in an oral capsule, an oral tablet, an oral suspension or an oralsolution, followed by administration of ganaxolone via one or moreintravenous bolus injection(s), followed by administration of ganaxolonevia a continuous intravenous infusion, and followed by administration ofganaxolone orally, e.g., in an oral capsule, an oral tablet, an oralsuspension or an oral solution, etc.

c. Additional Details and Guidance for Practicing the Method

The amount of ganaxolone administered intravenously in the methods ofthe present invention may vary, e.g., from about 0.25 mg to about 3000mg (e.g., about 1 mg, 2 mg, 3 mg, 4 mg, 5, mg, 7.5 mg, 10 mg, 15 mg, 20mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg,140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg,250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 325 mg, 350 mg, 375 mg,400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg,625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 725 mg, 750 mg, 775 mg, 800 mg,850 mg, 900 mg, 950 mg, 1000 mg, etc.).

The total daily dose of ganaxolone administered in the methods of thepresent invention may vary from about 450 mg to about 1000 mg. Incertain embodiments, the total daily dose of ganaxolone is from about500 mg to about 900 mg, from about 500 mg to about 875 mg, from about525 mg to about 875 mg, from about 525 mg to about 850 mg, from about525 mg to about 825 mg, from about 525 mg to about 800 mg, from about525 mg to about 775 mg, from about 525 mg to about 750 mg, or from about525 mg to about 725 mg.

In certain embodiments, the amount of ganaxolone administered is basedon the subject's weight. A subject weighing less than 40 kg, may receivea bolus dose from about 0.07 mg/kg to about 1.43 mg/kg (e.g., from about0.125 mg/kg to about 0.4 mg/kg) (over 1 to 5 minutes); and, thereafter,a continuous infusion at a rate from about 0.8 mg/kg/hour to about 2mg/kg/hour for about 1 to 3 hours; and, thereafter, a continuousinfusion at a rate from about 0.6 mg/kg/hour to about 1 mg/hr for about4 to 8 hours; and, thereafter, at a rate from about 0.15 mg/kg/hour toabout 0.4 mg/kg/hour for 13 to 19 hours. At the end of the 24 hours ofcontinuous infusion, the infusion rate may be increased to, e.g., a ratefrom about 0.2 mg/kg/hour to about 0.6 hour for 24 to 48 hours or 24 to96 hours. The dose may then be tampered by 10 to 25% every 6 hours andthen discontinued. In some embodiments, the dose is reduced by about 25%every 6 hours (75%, 50%, and 25%) and then discontinued. In someembodiments, the taper is from 12 to 24 hours.

A subject weighing 40 kg or more, may receive a bolus dose from about 5mg to about 100 mg (over about 1 to 5 minutes), and then a continuousinfusion from about 60 mg/hour to about 160 mg/hour for 1 to 4 hours;followed by a continuous infusion rate from about 20 mg/hour to about140 mg/hour for 4 to 8 hours; and, thereafter, at a rate from about 10mg/hour to about 120 mg/hour for 12 to 19 hours. At the end of the first24 hours of continuous infusion, the infusion rate may be increased for24 to 48 hours or 24 to 96 hours. The dose may then be tampered by 10 to25% every 6 hours and then discontinued. In some embodiments, the doseis reduced by about 25% every 6 hours (75%, 50%, and 25%) and thendiscontinued. In some embodiments, the taper is from 12 to 24 hours.

In certain embodiments, the methods of the invention compriseadministering some or all of the doses of ganaxolone in the form ofnanoparticles. Preparation and compositions of the exemplarynanoparticles are described in the Formulation section below.

In the embodiments, where the subject receives the drug for less than 2hours or progresses to an IV anesthetic drug (a 3rd line treatment) forseizure suppression, tapering of the dose is not required, and themethods of the invention do not comprise a tapering step.

In some methods of the invention, ganaxolone dose, or a portion thereof,is administered through a dedicated (peripheral or central) IV line.

The duration of treatment may vary, e.g., from about 30 minutes to about120 hours. In certain embodiments, the treatment duration is about 1 toabout 5 days (e.g., about 24 hours, about 36 hours, about 48 hours,about 72 hours, about 96 hours, or about 120 hours). In certainembodiments, the treatment includes a taper period of from about 10hours to about 24 hours (e.g., an 18-hour taper). In certainembodiments, treatment is continued until the subject achieves a seizureburden improvement of about 100.

Seizure burden is defined by the number of seizures in the entireduration of the EEG collection during the first 2 days of treatment.This will be compared to the seizure burden from the pre-dose EEG (up to24 hours prior to study drug initiation through immediately prior tostudy drug administration). If a pre-dose EEG is not available thecalculation should be done from the start of the EEG collection throughthe end of the first 2 days.

In certain embodiments, seizure burden assessed as duration ofelectrographic seizure activity per hour of EEG recording collected.

In certain embodiments, the seizure burden improvement is calculatedabout 12 to about 60 hours after the initiation of therapy.

If the seizure burden calculation indicates that the subject is unlikelyto benefit from additional administration (e.g., if the partial seizureburden improvement is about 100%), the dosage may be tapered over 12 to24 hours (e.g., 18 hours). Conversely, if the seizure burden calculationindicates that the subject may likely to benefit (e.g., if the partialseizure burden improvement is between 33-50%), administration ofganaxolone will continue for an additional time period (e.g., 24 to 48hours). At the end of the additional time period, the subject may bereassessed and/or the dose of ganaxolone may be tapered over 12 to 24hours (e.g., 18 hours).

For subjects who receive study drug for less than 2 hours and/or if atany time during study drug administration the subject progresses to anIV anesthetic (a 3rd line treatment) for seizure suppression no dosetaper is required.

A. Methods for Treating SE

The disclosure relates to methods for treating SE comprisingadministering to a subject in need thereof an intravenous bolus ofganaxolone and a continuous intravenous infusion of ganaxolone.Preferred methods for treating SE comprise administering to a subject anintravenous bolus of ganaxolone in an amount sufficient to suppress SEand a continuous intravenous infusion for continued SE suppression. SEpresents as a prolong seizure for a period of at least 5 minutes orwithout recovery between seizures. Suppression of SE typically breaksthe seizures (i.e., suppresses or reduces the seizure activity).Clinically, suppression of SE can be reduction in seizure burden (i.e.,the percent of time during which there is electrographic seizureactivity). For instance, a clinician may consider a seizure burden lessthan 20% suppression of SE and/or a seizure burden that is at least 50%less than during the 30 minutes prior to the initiation of treatment(i.e., intravenous bolus plus continuous intravenous infusion).

The human subject might be male, female, adults, and children, seniors(65 and older). The human subject may be, e.g., from about 1 year toabout 120 years old, from about 1 year to about 100 years old, fromabout 2 years to about 95 years old, from about 5 years to about 90years old, from about 7 years to about 85 years old, from about 10 yearsold to about 85 years old, from about 12 years old to about 85 yearsold, from about 14 years old to about 85 years old, from about 16 yearsold to about 85 years old, from about 18 years old to about 85 yearsold, or from about 20 years old to about 85 years old.

SE can be classified into three subtypes: generalized convulsive SE,non-convulsive SE, and refractory SE. Generalized convulsive statusepilepticus is the most commonly encountered form of SE and ischaracterized by convulsions that are associated with tonic-clonicmovements of the extremities and mental status impairment. NonconvulsiveSE is defined as SE activity seen on EEG without clinical symptoms.Refractory SE occurs in subjects who do not respond to the standard SEtreatment regimen of a first-line treatment and a second-line treatment.Each of these sub-types are suitable for treatment according to themethods described herein.

A subject suitable for treatment according to the methods describedherein has and/or is experiencing status epilepticus. For example, butnot limited to a generalized convulsive status epilepticus,non-convulsive status epilepticus, early status epilepticus, establishedstatus epilepticus, refractory status epilepticus, or super-refractorystatus epilepticus. A subject having refractory SE is particularlysuitable for the treatment according to the methods described herein.

Treatment of SE typically occurs in stages, first-line, second-line, andthird-line. The first-line standard of case treatment is parentalbenzodiazepines. Exemplary benzodiazepines include but are not limitedto clonazepam, lorazepam, midazolam, and diazepam. Benzodiazepines areineffective in about 35%-45% of cases. If SE continues despite treatmentwith benzodiazepines, other anti-seizure medications (e.g.,fosphenytoin, levetiracetam, and valproate) are administered as asecond-line treatment. In approximately 50% of cases are refractory tosecond-line treatment. In instances when SE continues despite first-lineand second-line treatment, general anesthetics (e.g., thiopental,propofol, and midazolam) are used as third-line treatment. About 31%-41%of subjects with SE develop refractory SE. The use of third-line agentsusually result in iatrogenic coma, which necessitates protection of theairways by intubation and mechanical ventilation. Further, use ofgeneral anesthetics is associated with high morbidity and approximately35% mortality.

In embodiments, the SE subject to be treated in accordance with themethods provided herein has failed first-line treatment, second-linetreatment, or third-line treatment. In other embodiments, the SE subjectto be treated has failed first-line treatment and second-line treatment.In other embodiments, the SE subject to be treated has failed first-linetreatment, second-line treatment and third-line treatment. A subjecthaving SE can be treated according to the methods provided herein priorto receiving other treatments, such as standard of care first-line orsecond-line treatments. Alternatively the subject can be treatedaccording to the methods provided herein after failure of first-linetreatment (e.g., benzodiazepines). In some instances, the subject is tobe treated according to the methods provided herein after failure ofsecond-line treatment (e.g., an anti-seizure drug). The subject to betreated according to the methods provided herein may have failed one ormore anti-seizure drugs. In other instances, the subject to be treatedaccording to the methods provided herein may have failed third-linetreatment (e.g., anesthetics). The subject to be treated according tothe methods disclosed herein may have failed first-line treatment (e.g.,benzodiazepine) and two or more second line second-line treatments. Forinstance, the subject may have failed two or more anti-seizure drugs.Exemplary anti-seizure drugs can include, but are not limited to,fosphenytoin/phenytoin, valproic acid, levetiracetam, lacosamide, orbrivaracetam.

Super refractory status epilepticus is characterized by status epilepticseizures that persist despite treatment with a first line therapy, asecond line therapy, and a general anesthetic for 24 hours or more.These patients are severely ill and will likely die without any furtherintervention. To treat these patients, it is recognized that a largeramount of ganaxolone may be required. To successfully treat thesesubjects according to the methods described herein an intravenous bolusof ganaxolone is administered to achieve a ganaxolone plasmaconcentration of about 800 mg/ml to about 1200 mg/ml and a continuousintravenous infusion of ganaxolone in an amount to achieve a ganaxoloneplasma concentration of about 800 mg/ml to about 1200 mg/ml.

In certain embodiments, the subject does not have a refractory geneticcondition selected from the group consisting of PCDH19-related epilepsy,CDKL5 Deficiency Disorder (CDD), Dravet Syndrome, Lennox-Gastautsyndrome (LGS), Continuous Sleep Wave in Sleep (CSWS), Epileptic StatusEpilepticus in Sleep (ESES), and other intractable and refractorygenetic epilepsy conditions that clinically resemble PCDH19-relatedepilepsy, CDKL5 Deficiency Disorder, Dravet Syndrome, LGS, CSWS, andESES. In certain embodiments, the subject does not have CDKL5 genedisorder. In certain embodiments, the subject does not havePCDH19-related epilepsy.

B. Ganaxolone

Ganaxolone (alternatively known as3α-hydroxy-3β-methyl-5α-pregnan-20-one, SPT3162, MD 9150000, CCD-1042,Mepalon, and 1042) is the subject of Investigational New DrugApplication (IND) No. 129,433. The molecular formula of ganaxolone isC₂₂H₃₆O₂, and the chemical structure is:

Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) is a 3β-methylatedsynthetic analogue of the endogenous neurosteroid allopregnanolone withsimilar biological activity (Carter et al., (1997), The Journal ofPharmacology and Experimental Therapeutics, 280:1284-1295), but it isdesigned to not activate nuclear (classical) progesterone receptors.Also, in contrast to allopregnanolone, ganaxolone is orallybioavailable.

Ganaxolone acts as a positive allosteric modulator of γ-aminobutyricacid type A (GABA_(A)) receptors in the CNS (Carter et al 1997).Ganaxolone affects GABA_(A) receptors by interacting with a recognitionsite that is distinct from other allosteric GABA_(A) receptormodulators, such as benzodiazepines and barbiturates. Ganaxolone bindsto synaptic- and extrasynaptic receptors, mediating both phasic andtonic modulation, respectively. The unique binding of ganaxolone tothese two distinct receptor types does not lead to the tolerance seenwith benzodiazepines (Mares and Stehlikova (2010) Neurosci. Let.469:396-399) and allows ganaxolone to act as a broad-spectrum GABAergiccompound with the potential to treat the myriad of symptoms related topediatric genetic epilepsies, refractory seizures, cognitive andbehavioral disorders, and sleep dysfunction.

Ganaxolone provides an alternative mechanism in the treatment ofseizures and could serve as effective therapy in the management of SE,including generalized convulsive status epilepticus, non-convulsivestatus epilepticus, early status epilepticus, established statusepilepticus, refractory status epilepticus, or super-refractory statusepilepticus.

Ganaxolone does not activate the progesterone receptor directly orindirectly, via metabolic conversion, confirming ganaxolones lack ofhormonal activity.

Ganaxolone has the advantage of controlling both convulsive andnon-convulsive seizures. In experimental animals, Ganaxolone producedimmediate and prolonged cessation of benzodiazepine-resistant SE asevidenced by a block of convulsions, reduction of EEG seizure activity,and increased survival.

Ganaxolone is insoluble in water. Its solubility in 95% alcohol,propylene glycol and polyethylene glycol are 13 mg/mL, 3.5 mg/mL and 3.1mg/mL, respectively. Ganaxolone has a relatively longhalf-life—approximately 20 hours in human plasma following oraladministration (Nohria, V. and Giller, E., Neurotherapeutics, (2007)4(1): 102-105). Furthermore, ganaxolone has a short T_(max), which meansthat therapeutic blood levels are reached quickly.

Ganaxolone is metabolized by CYP3A4/5, and in vitro data and human PKdata from subjects taking strong CYP inducers (carbamazepine andphenytoin) has shown increased ganaxolone clearance with approximately a45% lowering in overall ganaxolone levels and exposure.

In the ganaxolone development program overall, no clinically significanttrends in electrocardiogram (ECG) intervals, vital signs, or physical orneurological examinations have been noted, and no mean changes frombaseline in clinical laboratory results have been identified. In thecompleted placebo-controlled Phase 1, 2, and 3 studies, 0.32% ofsubjects who received ganaxolone and 0.46% of subjects who receivedplacebo developed elevated LFTs during the study (>3× ULN AST and/orALT). A subject participating in the ganaxolone paediatric epilepsystudy developed liver failure, which was not considered to be related toganaxolone. The subject was diagnosed with short bowel syndrome, liversteatosis and IgG-cholangitis, which were considered to be the causalfactors for the subject's liver failure. There have been no other casesof Hy's Law or liver failure in the ganaxolone development program. Itis known that ganaxolone and its metabolites are excreted to breastmilk. After cessation of the dosing, plasma ganaxolone levels areexpected to drop rapidly, but it is possible that low sub-therapeuticlevels persist for several days as ganaxolone is slowly released fromtissues.

Previous toxicology studies in animals focusing on prenatal and neonataldevelopment have not demonstrated toxicities associated with ganaxolone.Ganaxolone has been administered to infants with severe forms ofepilepsy as early as 4 months of age. In clinical trials involvingadministration of ganaxolone over several weeks, the study drug has beentapered off over a 1 to 2-week period. There have been no reports ofwithdrawal symptoms emerging after cessation of ganaxolone.

D. Formulations

Contemplated herein are formulations that comprise a therapeuticallyeffective amount of a neurosteroid for treating status epilepticusaccording the methods disclosed herein. Preferably the neurosteroid isganaxolone. Other neurosteroid that can be used according to the methodsdisclosed herein include, but are not limited, to allopregnanolone,3α-Dihydroprogesterone, 5α-Dihydroprogesterone, 5β-Dihydroprogesterone,Allopregnanediol, Dihydrodeoxycorticosterone, Pregnanediol,Pregnanolone, Tetrahydrodeoxycorticosterone, Alfadolone, Alfadoloneacetate, EIDD-036, Hydroxydione, Minaxolone,21-chloro-2β-morpholin-4-yl-5β-pregnan-3α-ol-20-one,2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-ylmethanesulfonate, or Renanolone, SGE-516, SGE-872, SAGE-217 (Zuranolone:3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one).

The formulation is preferably an intravenous formulation of ganaxolone.The intravenous formulation of ganaxolone can comprise a cyclodextrin(e.g., a sulfobutyl ether β-cyclodextrin (Captisol®). The IV solutioncan comprise a sterile ready to administer solution containing 1 mg/mlganaxolone in Captisol® (Captisol®:GNX ratio 60:1). The ready toadminister solution can comprise 1 mg/ml ganaxolone in sulfobutyl etherβ-cyclodextrin (Captisol®), a Captisol to ganaxolone ratio of 60:1, anda buffer (i.e., phosphate and/or sodium chloride). In embodiments, theIV solution is a sterile solution containing 3 mg/ml ganaxolone inCaptisol® (Sulfobutylether-β-Cyclodextrin) (Captisol®: GNX ratio 70:1)or 5 mg/ml ganaxolone in Captisol, each of which may or may not be maybe diluted with 0.9% saline (i.e., sodium chloride) solution, forexample to produce a 1 mg/ml ganaxolone solution for administration,prior to administration.

In certain embodiments, the formulation (e.g., an intravenousformulation) comprises ganaxolone and sulfobutylether-β-cyclodextrin(e.g., Captisol®) in a weight ratio from about 1:50 to about 1:75. Insome of these embodiments, the weight ratio ganaxolone and Captisol® isabout 1:51, about 1:52, about 1:53, about 54:1, about 1:55, about 1:56,about 1:57, about 1:58, about 1:59, about 1:60, about 1:61, about 1:62,about 1:63, about 1:64, about 1:65, about 1:66, about 1:67, about 1:68,about 1:69, about 1:70, about 1:71, or about 1:72. In some of theseembodiments, the weight ratio ganaxolone and Captisol® is about 1:60.

The intravenous formulation may be selected, e.g., from the groupconsisting of nanocrystal formulations; emulsions; lyocells; solvents orsurfactants; liposomes; microemulsions; and liquids containingsolid-lipid nanoparticles.

In certain embodiments, the intravenous formulation is an IV solution.An intravenous formulation is preferably a sterile liquid (e.g., aqueousliquid in the form of an emulsion, a suspension, a solution and thelikes). In some of these embodiments, the IV solution comprisesganaxolone and a pharmaceutically acceptable solvent(s) and/or oil(s)that can solubilize ganaxolone.

In certain embodiments, the intravenous formulation is an oil-in-wateremulsion.

In certain embodiments, the intravenous formulation is a liquidnanoparticulate formulation (e.g., a liquid comprising nanoparticles ofganaxolone). In some of the embodiments, the nanoparticulate formulationcomprises ganaxolone and a polymeric and/or ionic stabilizer, and isfree from complexing agents. In certain embodiments, the polymeric andionic stabilizers are selected from the group consisting of surfactants.In certain embodiments, surfactants are selected from the groupconsisting of sorbitan esters, polyoxyethylene sorbitan fatty acidesters, poloxamers, cholesterol salts, and bile salts.

In certain embodiments, the formulation for the intravenous infusion maybe a formulation as described and prepared in U.S. Patent PublicationNo. 2017/0258812 or U.S. Patent Publication No. 2016/0228454. However,formulations for the intravenous infusion may be prepared in accordancewith other methods known to those skilled in the art.

As described in U.S. Patent Publication No. 2016/0228454, an aqueousinjectable ganaxolone formulation may comprise a) ganaxolone andsulfobutyl ether-β-cyclodextrin in an inclusion complex; and b) water.In some embodiments, the complex comprising ganaxolone and sulfobutylether-β-cyclodextrin comprises a 1:1 ganaxolone:sulfobutylether-β-cyclodextrin complex; and the w/w ratio of sulfobutylether-β-cyclodextrin to ganaxolone is about 52:1 or greater. In someembodiments, the formulation may further comprise surfactant. In someembodiments, the surfactant is a sorbitan ester, a polyoxyethylenesorbitan fatty acid ester, a poloxamer, a cholesterol salt, or a bilesalt. In some embodiments, the surfactant may comprise from about 1 toabout 15 percent of the formulation by weight. In some embodiments, thesurfactant is polysorbate 80. In some embodiments, the formulationfurther comprises a buffer and has a pH of about 6.0 to about 7.6. Insome embodiments, the buffer is a phosphate buffer. In some embodiments,the buffer is a combination of a monobasic phosphate buffer and adibasic phosphate buffer, wherein the concentration of each phosphatebuffer is 2 mM to 50 mM. In some embodiments, the buffer is a phosphatebuffer. In some embodiments, the buffer is a combination of a monobasicphosphate buffer and a dibasic phosphate buffer, wherein theconcentration of each phosphate buffer is 2 mM to 50 mM. In someembodiments, the concentration of ganaxolone is 2 mg/ml to 8 mg/ml, thew/w ratio of sulfobutyl ether-β-cyclodextrin to ganaxolone is within therange from about 52:1 to about 90:1; the formulation contains a bufferand has a pH of 6.7 to 7.3 or a pH of 6.0 to 7.0; and the formulationcontains from 1 to 15 weight percent surfactant. In some embodiments,the concentration of ganaxolone is 1 mg/ml to 5 mg/ml; the weightpercent of sulfobutyl ether-β-cyclodextrin 25% to 35%; and theformulation contains from 5% to 15% (weight percent) of at least one ofthe following: a surfactant, ethanol, glycerin, or propylene glycol. Insome embodiments, the formulation further comprises a preservative. Insome embodiments, the preservative is benzyl alcohol, chlorbutanol,2-ethoxyethanol, parabens (including methyl, ethyl, propyl, butyl, andcombinations), benzoic acid, sorbic acid, chlorhexidene, phenol,3-cresol, thimerosal, or a phenylmercurate salt.

As further described in U.S. Patent Publication No. 2016/0228454, theformulation may be a lyophilized ganaxolone formulation comprisingganaxolone and sulfobutyl ether-β-cyclodextrin, wherein the ganaxoloneformulation is 1.0% to 1.5% ganaxolone. In some embodiments, theformulation may further comprise a bulking agent. In some embodiments,the bulking agent is mannitol, lactose, sucrose, trehalose, sorbitol,glucose, rafinose, glycine, histidine, polyethylene glycol (PEG), orpolyvinyl pyrrolidone (PVP).

Ganaxolone formulations suitable for parenteral administration in themethods of the present invention may comprise physiologically acceptablesterile aqueous or non-aqueous solutions, dispersions, suspensions oremulsions, and sterile powders for reconstitution into sterileinjectable solutions or dispersions. Examples of suitable aqueous andnon-aqueous carriers, diluents, solvents, or vehicles including water,ethanol, polyols (propylene glycol, polyethylene-glycol, glycerol,cremophor and the like), suitable mixtures thereof, vegetable oils (suchas olive oil) and injectable organic esters such as ethyl oleate.Additionally, ganaxolone can be dissolved at concentrations of >1 mg/mlusing water soluble beta cyclodextrins (e.g.beta-sulfobutyl-cyclodextrin and 2-hydroxypropylbetacyclodextrin). Aparticularly suitable cyclodextrin is a substituted-β-cyclodextrin isCaptisol®. Proper fluidity can be maintained, for example, by the use ofa coating such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.Ganaxolone formulations suitable for subcutaneous injection may alsocontain additives such as preserving, wetting, emulsifying, anddispensing agents. Prevention of the growth of microorganisms can beensured by various antibacterial and antifungal agents, such asparabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, sorbicacid, and the like. It may also be desirable to include isotonic agents,such as sugars, sodium chloride, and the like. Prolonged drug absorptionof the injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, such as aluminum monostearate and gelatin.Ganaxolone suspension formulations designed for extended release viasubcutaneous or intramuscular injection can avoid first pass metabolismand lower dosages of ganaxolone will be necessary to maintain plasmalevels of about 50 ng/ml. In such formulations, the particle size of theganaxolone particles and the range of the particle sizes of theganaxolone particles can be used to control the release of the drug bycontrolling the rate of dissolution in fat or muscle.

In certain embodiments, the intravenous formulation is a solutioncomprising a complexing agent(s). In some of these embodiments, acomplexing agent is a molecule with a lipophilic core and hydrophilicouter shell capable of solubilizing ganaxolone

In certain embodiments, the formulation is an IV solution comprisingganaxolone and sulfobutylether cyclodextrin (Captisol®), whereinganaxolone is solubilized in sulfobutylether cyclodextrin (Captisol®).In some embodiments, the solution comprises 3 mg of ganaxolone per 1 mlof the solution and is sterile. In certain embodiments, the solution isstable for at least 18 months, is stored refrigerated at a temperaturefrom about 4° C. to about 8° C.

In certain embodiments, the liquid formulation of the present inventionmay be a formulation as described and prepared in U.S. Pat. No.8,022,054, entitled “Liquid Ganaxolone Formulations and Methods for theMaking and Use Thereof” However, the oral liquid (e.g., suspension)formulation of ganaxolone may be prepared in accordance with othermethods known to those skilled in the art.

As described in U.S. Pat. No. 8,022,054, the liquid formulation may bean aqueous dispersion of stabilized particles comprising ganaxolone, ahydrophilic polymer, a wetting agent, and an effective amount of acomplexing agent that stabilizes particle growth after an initialparticle growth and endpoint is reached, the complexing agent selectedfrom the group of small organic molecules having a molecular weight lessthan 550 and containing a moiety selected from the group consisting of aphenol moiety, an aromatic ester moiety and an aromatic acid moiety,wherein the stabilized particles have a volume weighted median diameter(D50) of the particles from about 50 nm to about 500 nm, the complexingagent being present in an amount from about 0.05% to about 5%, w/w basedon the weight of particles, the particles dispersed in an aqueoussolution which further contains at least two preservatives in an amountsufficient to inhibit microbial growth. The hydrophilic polymer may bein an amount from about 3% to about 50%, w/w, based on the weight of thesolid particles. The wetting agent may be an amount from about 0.01% toabout 10%, w/w, based on the weight of the solid particles. Ganaxolonemay be in an amount from about 10% to about 80% (and in certainembodiments form about 50% to about 80%) based on the weight of thestabilized particles. The stabilized particles may exhibit an increasein volume weighted median diameter (D50) of not more than about 150%when the particles are dispersed in simulated gastric fluid (SGF) orsimulated intestinal fluid (SIF) at a concentration of 0.5 to 1 mgganaxolone/mL and placed in a heated bath at 36° to 38° C. for 1 hour ascompared to the D50 of the stabilized particles when the particles aredispersed in distilled water under the same conditions, wherein thevolume weighted median diameter (D50) of the stabilized particlesdispersed in SGF or SIF is less than about 750 nm. The stabilizedparticles may exhibit an increase in volume weighted median diameter(D50) of not more than about 150% when the formulation is dispersed in15 mL of SGF or SIF at a concentration of 0.5 to 1 mg ganaxolone/mL ascompared to the D50 of the stabilized particles when the particles aredispersed in distilled water under the same conditions, wherein thevolume weighted median diameter (D50) of the stabilized particlesdispersed in SGF or SIF is less than about 750 nm.

The complexing agent can be any molecule with a lipophilic core andhydrophilic outer shell capable of solubilizing ganaxolone. In certainembodiments, complexing agent can be a substance containing a phenolmoiety, an aromatic ester moiety or an aromatic acid moiety. In certainembodiments, complexing agents are selected from the group consisting ofparabens, organic acids, carboxylic acids, aromatic acids, aromaticesters, acid salts of amino acids, methyl anthranilate, sodiummetabisulphite, ascorbic acid and its derivatives, malic acid,isoascorbic acid, citric acid, tartaric acid, sodium sulphite, sodiumbisulphate, tocopherol, water- and fat-soluble derivatives oftocopherol, sulphites, bisulphites and hydrogen sulphites,para-aminobenzoic acid and esters,2,6-di-t-butyl-alpha-dimethylamino-p-cresol, t-butylhydroquinone,di-t-amylhydroquinone, di-t-butylhydroquinone, butylhydroxytoluene(BHT), butylhydroxyanisole (BHA), pyrocatechol, pyrogallol,propyl/gallate, nordihydroguaiaretic acid, phosphoric acids, sorbic andbenzoic acids, esters, ascorbyl palmitate, derivatives and isomericcompounds thereof, pharmaceutically acceptable salts thereof, andmixtures thereof. In certain embodiments, the complexing agent isselected from the group consisting of a paraben, benzoic acid, phenol,sodium benzoate, methyl anthranilate, and the like. The hydrophilicpolymer may be a cellulosic polymer, a vinyl polymer and mixturesthereof. The cellulosic polymer may be a cellulose ether, e.g.,hydroxypropymethylcellulose. The vinyl polymer may be polyvinyl alcohol,e.g., vinyl pyrrolidone/vinyl acetate copolymer (S630). The wettingagent may be sodium lauryl sulfate, a pharmaceutically acceptable saltof docusate, and mixtures thereof. The aqueous dispersion may furthercomprise a sweetener, e.g., sucralose. In certain embodiments, thepreservative is selected from the group consisting of potassium sorbate,methylparaben, propylparaben, benzoic acid, butylparaben, ethyl alcohol,benzyl alcohol, phenol, benzalkonium chloride, and mixtures of any ofthe foregoing.

In some embodiments, liquid ganaxolone formulations are providedcomprising the ganaxolone particles described herein and at least onedispersing agent or suspending agent for oral administration to asubject. The ganaxolone formulation may be a powder and/or granules forsuspension, and upon admixture with water, a substantially uniformsuspension is obtained. As described herein, the aqueous dispersion cancomprise amorphous and non-amorphous ganaxolone particles of consistingof multiple effective particle sizes such that ganaxolone particleshaving a smaller effective particle size are absorbed more quickly andganaxolone particles having a larger effective particle size areabsorbed more slowly. In certain embodiments, the aqueous dispersion orsuspension is an immediate release formulation. In another embodiment,an aqueous dispersion comprising amorphous ganaxolone particles isformulated such that about 50% of the ganaxolone particles are absorbedwithin about 3 hours after administration and about 90% of theganaxolone particles are absorbed within about 10 hours afteradministration. In other embodiments, addition of a complexing agent tothe aqueous dispersion results in a larger span of ganaxolone containingparticles to extend the drug absorption phase such that 50-80% of theparticles are absorbed in the first 3 hours and about 90% are absorbedby about 10 hours.

A suspension is “substantially uniform” when it is mostly homogenous,that is, when the suspension is composed of approximately the sameconcentration of ganaxolone at any point throughout the suspension.Preferred embodiments are those that provide concentrations essentiallythe same (within 15%) when measured at various points in a ganaxoloneaqueous oral formulation after shaking. Especially preferred are aqueoussuspensions and dispersions, which maintain homogeneity (up to 15%variation) when measured 2 hours after shaking. The homogeneity shouldbe determined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

In some embodiments, ganaxolone formulations are powders for aqueousdispersion and comprise stable ganaxolone particles having an effectiveparticle size by weight of less than 500 nm formulated with ganaxoloneparticles having an effective particle size by weight of greater than500 nm. In such embodiments, the formulations have a particle sizedistribution wherein about 10% to about 100% of the ganaxolone particlesby weight are between about 75 nm and about 500 nm, about 0% to about90% of the ganaxolone particles by weight are between about 150 nm andabout 400 nm, and about 0% to about 30% of the ganaxolone particles byweight are greater than about 600 nm. The ganaxolone particles describeherein can be amorphous, semi-amorphous, crystalline, semi-crystalline,or mixture thereof.

In one embodiment, the aqueous suspensions or dispersions describedherein comprise ganaxolone particles or ganaxolone complex at aconcentration of about 20 mg/ml to about 150 mg/ml of suspension. Inanother embodiment, the aqueous oral dispersions described hereincomprise ganaxolone particles or ganaxolone complex particles at aconcentration of about 25 mg/ml to about 75 mg/ml of solution. In yetanother embodiment, the aqueous oral dispersions described hereincomprise ganaxolone particles or ganaxolone complex at a concentrationof about 50 mg/ml of suspension. The aqueous dispersions describedherein are especially beneficial for the administration of ganaxolone toinfants (less than 2 years old), children under 10 years of age and anypatient group that is unable to swallow or ingest solid oral dosageforms.

Liquid ganaxolone formulation for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, and syrups. See, e.g., Singh et al., Encyclopedia ofPharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). In addition toganaxolone particles, the liquid dosage forms may comprise additives,such as: (a) disintegrating agents; (b) dispersing agents; (c) wettingagents; (d) at least one preservative, (e) viscosity enhancing agents,(f) at least one sweetening agent, (g) at least one flavoring agent, (h)a complexing agent, and (i) an ionic dispersion modulator. In someembodiments, the aqueous dispersions can further comprise a crystallineinhibitor.

Examples of disintegrating agents for use in the aqueous suspensions anddispersions include, but are not limited to, a starch, e.g., a naturalstarch such as corn starch or potato starch, a pregelatinized starchsuch as National 1551 or Amijele®, or sodium starch glycolate such asPromogel® or Explotab®; a cellulose such as a wood product,microcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102,Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose; a cross-linked starch such as sodium starch glycolate; across-linked polymer such as crosspovidone; a cross-linkedpolyvinylpyrrolidone; alginate such as alginic acid or a salt of alginicacid such as sodium alginate; a clay such as Veegum® HV (magnesiumaluminum silicate); a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth; sodium starch glycolate; bentonite; a naturalsponge; a surfactant; a resin such as a cation-exchange resin; citruspulp; sodium lauryl sulfate; sodium lauryl sulfate in combinationstarch; and the like.

In some embodiments, the dispersing agents suitable for the aqueoussuspensions and dispersions described herein are known in the art andinclude, for example, hydrophilic polymers, electrolytes, Tween® 60 or80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®),and the carbohydrate-based dispersing agents such as, for example,hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC,HPC-SL, and HPC-L), hydroxypropylmethylcellulose andhydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMCK15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate stearate, noncrystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA),polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®, e.g., S-630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); and poloxamines (e.g., Tetronic 9080, also known asPoloxamine 9080, which is a tetrafunctional block copolymer derived fromsequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)). In otherembodiments, the dispersing agent is selected from a group notcomprising one of the following agents: hydrophilic polymers;electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP);hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M,and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium;methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulosephthalate; hydroxypropylmethyl-cellulose acetate stearate;non-crystalline cellulose; magnesium aluminum silicate; triethanolamine;polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®,F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); or poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908%).

Wetting agents (including surfactants) suitable for the aqueoussuspensions and dispersions described herein are known in the art andinclude, but are not limited to, acetyl alcohol, glycerol monostearate,polyoxyethylene sorbitan fatty acid esters (e.g., the commerciallyavailable Tweens® such as e.g., Tween 20® and Tween 80® (ICI SpecialtyChemicals)), and polyethylene glycols (e.g., Carbowaxs 3350® and 1450®,and Carpool 934® (Union Carbide)), oleic acid, glyceryl monostearate,sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate,triacetin, vitamin E TPGS, sodium taurocholate, simethicone,phosphotidylcholine and the like.

Suitable preservatives for the aqueous suspensions or dispersionsdescribed herein include, for example, potassium sorbate, parabens(e.g., methylparaben and propylparaben) and their salts, benzoic acidand its salts, other esters of parahydroxybenzoic acid such asbutylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenoliccompounds such as phenol, or quaternary compounds such as benzalkoniumchloride. Preservatives, as used herein, are incorporated into thedosage form at a concentration sufficient to inhibit microbial growth.In one embodiment, the aqueous liquid dispersion can comprisemethylparaben and propylparaben in a concentration ranging from about0.01% to about 0.3% methylparaben by weight to the weight of the aqueousdispersion and 0.005% to 0.03% propylparaben by weight to the totalaqueous dispersion weight. In yet another embodiment, the aqueous liquiddispersion can comprise methylparaben 0.05 to about 0.1 weight % andpropylparaben from 0.01-0.02 weight % of the aqueous dispersion.

Suitable viscosity enhancing agents for the aqueous suspensions ordispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, Plasdone® S-630, carbomer, polyvinylalcohol, alginates, acacia, chitosans and combinations thereof. Theconcentration of the viscosity enhancing agent will depend upon theagent selected and the viscosity desired.

Examples of natural and artificial sweetening agents suitable for theaqueous suspensions or dispersions described herein include, forexample, acacia syrup, acesulfame K, alitame, anise, apple, aspartame,banana, Bavarian cream, berry, black currant, butterscotch, calciumcitrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon,bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa,cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose,eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate,glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon,lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol,mannitol, maple, marshmallow, menthol, mint cream, mixed berry,neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermintcream, Prosweet®. Powder, raspberry, root beer, rum, saccharin, safrole,sorbitol, spearmint, spearmint cream, strawberry, strawberry cream,stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame,acesulfame potassium, mannitol, talin, sucralose, sorbitol, Swiss cream,tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut,watermelon, wild cherry, wintergreen, xylitol, or any combination ofthese flavoring ingredients, e.g., anise-menthol, cherry-anise,cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon,lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint,and mixtures thereof. In one embodiment, the aqueous liquid dispersioncan comprise a sweetening agent or flavoring agent in a concentrationranging from about 0.0001% to about 10.0% the weight of the aqueousdispersion. In another embodiment, the aqueous liquid dispersion cancomprise a sweetening agent or flavoring agent in a concentrationranging from about 0.0005% to about 5.0% wt % of the aqueous dispersion.In yet another embodiment, the aqueous liquid dispersion can comprise asweetening agent or flavoring agent in a concentration ranging fromabout 0.0001% to 0.1 wt %, from about 0.001% to about 0.01 weight %, orfrom 0.0005% to 0.004% of the aqueous dispersion.

In addition to the additives listed above, the liquid ganaxoloneformulations can also comprise inert diluents commonly used in the art,such as water or other solvents, solubilizing agents, and emulsifiers.

In some embodiments, the ganaxolone formulations can be self-emulsifyingdrug delivery systems (SEDDS). Emulsions are dispersions of oneimmiscible phase in another, usually in the form of droplets. Generally,emulsions are created by vigorous mechanical dispersion. SEDDS, asopposed to emulsions or microemulsions, spontaneously form emulsionswhen added to an excess of water without any external mechanicaldispersion or agitation. An advantage of SEDDS is that only gentlemixing is required to distribute the droplets throughout the solution.Additionally, water or the aqueous phase can be added just prior toadministration, which ensures stability of an unstable or hydrophobicactive ingredient. Thus, the SEDDS provides an effective delivery systemfor oral and parenteral delivery of hydrophobic active ingredients.SEDDS may provide improvements in the bioavailability of hydrophobicactive ingredients. Methods of producing self-emulsifying dosage formsare known in the art include, but are not limited to, for example, U.S.Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate,sodium docusate, cholesterol, cholesterol esters, taurocholic acid,phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corngerm oil, olive oil, castor oil, and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters ofsorbitan, or mixtures of these substances, and the like.

In certain preferred embodiments, the liquid pharmaceutical formulationcomprising ganaxolone, hydroxypropyl methylcellulose, polyvinyl alcohol,sodium lauryl sulfate, simethicone, methyl paraben, propyl paraben,sodium benzoate, citric acid, and sodium citrate at pH 3.8-4.2. Thesuspension may comprise ganaxolone at a concentration of 50 mg/ml. Theformulation may further comprise a pharmaceutically acceptable sweetener(e.g., sucralose) and/or a pharmaceutically acceptable flavorant (e.g.,cherry). The formulation may be enclosed, e.g., in a 120 mL, 180 mL, 240mL, or 480 mL bottle.

A formulation for oral administration may be an oral solid dosage form(e.g., an oral capsule or tablet) or a liquid (e.g., an oral suspensioncomprising ganaxolone). In certain embodiments, the oral suspension isadministered to the patient via the use of an oral syringe.

In certain embodiments, the liquid formulation of the present inventionmay be a formulation as described and prepared in Applicant's prior U.S.Pat. No. 8,022,054, entitled “Liquid Ganaxolone Formulations and Methodsfor the Making and Use Thereof” However, the oral liquid (e.g.,suspension) formulation of ganaxolone may be prepared in accordance withother methods known to those skilled in the art.

In certain preferred embodiments, the oral solid formulation of thepresent invention may be a formulation as described and prepared inApplicant's prior U.S. Pat. No. 7,858,609, entitled “Solid GanaxoloneFormulations and Methods for the Making and Use Thereof.’ However, theoral solid dosage formulation of ganaxolone may be prepared inaccordance with other methods known to those skilled in the art.

For example, as disclosed in U.S. Pat. No. 7,858,609, the oral solidformulation may comprise stabilized particles comprising ganaxolone, ahydrophilic polymer, a wetting agent, and an effective amount of acomplexing agent that stabilizes particle growth after an initialparticle growth and endpoint is reached, the complexing agent being asmall organic molecule having a molecular weight less than 550 andcontaining a moiety selected from the group consisting of a phenolmoiety, an aromatic ester moiety and an aromatic acid moiety, whereinthe stabilized particles have a volume weighted median diameter (D50) ofthe particles is from about 50 nm to about 500 nm, the complexing agentbeing present in an amount from about 0.05% to about 5% w/w, based onthe weight particles of the solid. The hydrophilic polymer may be in anamount from about 3% to about 50%, w/w, based on the weight of the solidparticles. The wetting agent may be an amount from about 0.01% to about10%, w/w, based on the weight of the solid particles. Ganaxolone may bein an amount from about 10% to about 80% (and in certain embodimentsform about 50% to about 80%) based on the weight of the stabilizedparticles. The stabilized particles may exhibit an increase in volumeweighted median diameter (D50) of not more than about 150% when theparticles are dispersed in simulated gastric fluid (SGF) or simulatedintestinal fluid (SIF) at a concentration of 0.5 to 1 mg ganaxolone/mLand placed in a heated bath at 36° to 38° C. for 1 hour as compared tothe D50 of the stabilized particles when the particles are dispersed indistilled water under the same conditions, wherein the volume weightedmedian diameter (D50) of the stabilized particles dispersed in SGF orSIF is less than about 750 nm. The stabilized particles may exhibit anincrease in volume weighted median diameter (D50) of not more than about150% when the formulation is dispersed in 15 mL of SGF or SIF at aconcentration of 0.5 to 1 mg ganaxolone/mL as compared to the D50 of thestabilized particles when the particles are dispersed in distilled waterunder the same conditions, wherein the volume weighted median diameter(D50) of the stabilized particles dispersed in SGF or SIF is less thanabout 750 nm. The solid stabilized particles may be combined withoptional excipients and prepared for administration in the form of apowder, or they may be incorporated into a dosage form selected from thegroup consisting of a tablet or capsule. The complexing agent may be aparaben, benzoic acid, phenol, sodium benzoate, methyl anthranilate, andthe like. The hydrophilic polymer may be a cellulosic polymer, a vinylpolymer and mixtures thereof. The cellulosic polymer may be a celluloseether, e.g., hydroxypropymethylcellulose. The vinyl polymer may bepolyvinyl alcohol, e.g., vinyl pyrrolidone/vinyl acetate copolymer(S630). The wetting agent may be sodium lauryl sulfate, apharmaceutically acceptable salt of docusate, and mixtures thereof. Whenthe particles are incorporated into a solid dosage form, the soliddosage form may further comprise at least one pharmaceuticallyacceptable excipient, e.g., an ionic dispersion modulator, a watersoluble spacer, a disintegrant, a binder, a surfactant, a plasticizer, alubricant, a diluent and any combinations or mixtures thereof. The watersoluble spacer may be a saccharide or an ammonium salt, e.g., fructose,sucrose, glucose, lactose, mannitol. The surfactant may be, e.g.,polysorbate. The plasticizer may be, e.g., polyethylene glycol. Thedisintegrant may be cross-linked sodium carboxymethylcellulose,crospovidone, mixtures thereof, and the like.

A capsule may be prepared, e.g., by placing the bulk blend ganaxoloneformulation, described herein, inside of a capsule. In some embodiments,the ganaxolone formulations (non-aqueous suspensions and solutions) areplaced in a soft gelatin capsule. In other embodiments, the ganaxoloneformulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theganaxolone formulations are placed in a sprinkle capsule, wherein thecapsule may be swallowed whole or the capsule may be opened and thecontents sprinkled on food prior to eating. In some embodiments of thepresent invention, the therapeutic dose is split into multiple (e.g.,two, three, or four) capsules. In some embodiments, the entire dose ofthe ganaxolone formulation is delivered in a capsule form.

In certain embodiments, each capsule contains either 200 mg or 225 mgganaxolone, and hydroxypropyl methylcellulose, sucrose, polyethyleneglycol 3350, polyethylene glycol 400, sodium lauryl sulfate, sodiumbenzoate, citric acid anhydrous, sodium methyl paraben, microcrystallinecellulose, 30% Simethicone Emulsion, gelatin capsules, polysorbate 80,and sodium chloride. In some of the embodiments, the size of the capsuleis 00.

Alternatively, the oral dosage forms of the present invention may be inthe form of a controlled release dosage form, as described in U.S. Pat.No. 7,858,609.

In certain preferred embodiments, the oral solid formulation of thepresent invention may be a formulation as described and prepared U.S.Pat. No. 8,367,651.

As described in U.S. Pat. No. 8,367,651, solid stabilized particles maycomprise ganaxolone, a hydrophilic polymer, a wetting agent, and aneffective amount of a complexing agent that stabilizes particle growthafter an initial particle growth and endpoint is reached, the complexingagent being a small organic molecule having a molecular weight less than550 and containing a moiety selected from the group consisting of aphenol moiety, an aromatic ester moiety and an aromatic acid moiety,wherein the stabilized particles have a volume weighted median diameter(D50) of the particles is from about 50 nm to about 500 nm and theconcentration of ganaxolone in the solid stabilized particles is atleast 50% by weight. The hydrophilic polymer maybe in an amount fromabout 3% to about 50%, w/w, based on the weight of the solid particles.The wetting agent may be in an amount from about 0.01% to about 10%,w/w, based on the weight of the solid particles. In some of theembodiments, the stabilized particles exhibit an increase in volumeweighted median diameter (D50) of not more than about 150% when theparticles are dispersed in simulated gastric fluid (SGF) or simulatedintestinal fluid (SIF) at a concentration of 0.5 to 1 mg ganaxolone/mLand placed in a heated bath at 36° to 38° C. for 1 hour as compared tothe D50 of the stabilized particles when the particles are dispersed indistilled water under the same conditions, wherein the volume weightedmedian diameter (D50) of the stabilized particles dispersed in SGF orSIF is less than about 750 nm. In some embodiments, the stabilizedparticles exhibit an increase in volume weighted median diameter (D50)of not more than about 150% when the formulation is dispersed in 15 mLof SGF or SIF at a concentration of 0.5 to 1 mg ganaxolone/mL ascompared to the D50 of the stabilized particles when the particles aredispersed in distilled water under the same conditions, wherein thevolume weighted median diameter (D50) of the stabilized particlesdispersed in SGF or SIF is less than about 750 nm. In some embodiments,ganaxolone may be present in an amount greater than 50% to about 80%,based on the weight of the particles. In some embodiments, thestabilized particles may exhibit an increase in volume weighted mediandiameter (D50) of not more than about 150% when the particles aredispersed in simulated gastric fluid (SGF) or simulated intestinal fluid(SIF) at a concentration of 0.5 to 1 mg ganaxolone/mL and placed in aheated bath at 36° to 38° C. for 1 hour, as compared to the D50 of thestabilized particles when the particles are dispersed in distilled waterunder the same conditions, wherein the volume weighted median diameter(D50) of the stabilized particles dispersed in SGF or SIF is less thanabout 750 nm. In some embodiments, the solid stabilized particles may bein the form of a powder. In some embodiments, the particles may beincorporated into a dosage form selected from the group consisting of atablet or capsule. In some embodiments, the volume weighted mediandiameter (D50) of the stabilized particles dispersed in distilled wateris from about 100 nm to about 350 nm. In some embodiments, thecomplexing agent is selected from the group consisting of parabens,benzoic acid, methyl anthranilate, and pharmaceutically acceptable saltsthereof and mixtures thereof. In some embodiments, paraben is selectedfrom the group consisting of methylparaben, ethylparaben, propylparaben,pharmaceutically acceptable salts thereof and mixtures thereof. In someembodiments, the hydrophilic polymer is selected from the groupconsisting of a cellulosic polymer, a vinyl polymer and mixturesthereof. In some embodiments, the cellulosic polymer is a celluloseether. In some embodiments, the cellulose ether ishydroxypropylmethylcellulose. In some embodiments, the vinyl polymer ispolyvinyl alcohol. In some embodiments, the wetting agent is selectedfrom the group consisting of sodium lauryl sulfate, a pharmaceuticallyacceptable salt of docusate, and mixtures thereof. Is some embodiments,the particles are incorporated into a solid dosage form, furthercomprising at least one pharmaceutically acceptable excipient selectedfrom the group consisting of an ionic dispersion modulator, an watersoluble spacer, a disintegrant, a binder, a surfactant, a plasticizer, alubricant, and any combinations or mixtures thereof. In someembodiments, the pharmaceutically acceptable excipient comprises anionic dispersion modulator. In some embodiments, the ionic dispersionmodulator is in an amount from about 1% to about 50%, w/w, based on theweight of the solid particles. In some embodiments, the ionic dispersionmodulator is a salt. In some embodiments, the ionic dispersion modulatoris an inorganic salt is selected from the group consisting of amagnesium salt, a calcium salt, a lithium salt, a potassium salt, asodium salt and mixtures thereof. In some embodiments, the ionicdispersion modulator is an organic salt is selected from the groupconsisting of a citrate salt, a succinate salt, a fumarate salt, amalate salt, maleate salt, a tartrate salt, a glutarate salt, a lactatesalt and mixtures thereof. In some embodiments, the pharmaceuticallyacceptable excipient comprises a water soluble spacer. In someembodiments, the water soluble spacer is in an amount from about 2% toabout 60%, w/w, based on the weight of the solid particles. In someembodiments, the water soluble spacer is a saccharide or an ammoniumsalt. In some embodiments, the saccharide is selected from the groupconsisting of fructose, sucrose, glucose, lactose, mannitol and mixturesthereof. In some embodiments, the disintegrant is selected from thegroup consisting of cross-linked sodium carboxymethylcellulose,crospovidone and any combinations or mixtures thereof. In someembodiments, the surfactant is a polysorbate. In some embodiments, theplasticizer is polyethylene glycol. In some embodiments, the soliddosage form is an immediate release dosage form. In some embodiments,the solid dosage form is a controlled release dosage form. In someembodiments, the particles are incorporated into an oral solid dosageform comprising (i) a controlled release component comprising a firstportion of the stabilized particles; and a controlled release material,and (ii) an immediate release component comprising a second portion ofthe stabilized particles, the first and second portion of stabilizedparticles having a volume weighted median diameter (D50) of from about50 nm to about 500 nm. In some embodiments, the ratio of ganaxolone incontrolled release to immediate release is from about 4:1 to about 1:4.In some embodiments, the dosage form provides a therapeutic effect forabout 8 to about 24 hours after administration. In some embodiments, thecomplexing agent is in an amount from about 0.05% to about 5%, w/w,based on the weight of the solid particles. In some embodiments, thecomplexing agent comprises methylparaben or a salt thereof. In someembodiments, the complexing agent comprises benzoic acid or a saltthereof. In some embodiments, the complexing agent comprises methylanthranilate. In some embodiments, the formulation includes from about200 mg to about 800 mg ganaxolone.

As further described in U.S. Pat. No. 8,367,651, solid stabilizedparticles may also comprise ganaxolone, a hydrophilic polymer, a wettingagent, and an effective amount of a complexing agent selected from thegroup of small organic molecules having a molecular weight less than 550and containing a moiety selected from the group consisting of a phenolmoiety, an aromatic ester moiety and an aromatic acid moiety, thestabilized particles having a volume weighted median diameter (D50) ofthe particles from about 50 nm to about 500 nm, the concentration ofganaxolone in the solid stabilized particles being at least 50% byweight. In some embodiments, ganaxolone is present in an amount greaterthan 50% to about 80%, based on the weight of the particles. In someembodiments, the particles are incorporated into a dosage form selectedfrom the group consisting of a tablet or capsule. In some embodiments,the complexing agent is selected from the group consisting of parabens,benzoic acid, methyl anthranilate, and pharmaceutically acceptable saltsthereof and mixtures thereof.

In certain preferred embodiments, the formulation of the presentinvention may be a pharmaceutical composition described in U.S. Pat. No.9,029,355.

In certain embodiments, the composition may comprise the ganaxolonenanoparticles as described above, further in formulations as describedin U.S. Pat. No. 9,029,355. In some embodiments, the pharmaceuticalcomposition is a compressed tablet. In some embodiments, thepharmaceutical composition is contained inside a capsule.

E. Combination

In certain embodiments, an additional antiepileptic drug is administeredbefore, during or after the continuous intravenous infusion ofganaxolone. Examples of additional antiepileptic drugs that may beadministered are provided in the Additional Antiepileptic Drugs sectionbelow. In some embodiments, the additional antiepileptic drug may beselected from the group consisting benzodiazepines, phenytoin,fosphenytoin, valproic acid, phenobarbital, and/or levetiracetam. Insome embodiments, the antiepileptic drug is a benzodiazepine (e.g.,diazepam, lorazepam, etc.).

In certain embodiments, the additional antileptic drug administeredalong with ganaxolone is selected from the group consisting ofchlordesmethyldiazepam, loreclezole, methsuximide, dipropylacetamide,pheneturide, 2-fluoro-2-phenyl-1,3-propanediyl dicarbamate,ethylphenylhydantoin, 6-methoxytryptoline, N-desmethylclobazam,anthranilic acid, Org 2766, sulthiame, dimethadione,2-(2,3-dicarboxycyclopropyl)glycine, NCS 382, pipequaline, bretazenil,denzimol, stiripentol, progabide acid, brivaracetam, U 54494A,epidiolex, bromides, mephenytoin, ethosuximide, trimethadione,mebeverine, 5-(2-cyclohexylidene-ethyl)-5-ethylbarbiturate,2-propyl-2-pentenoic acid, neo-kyotorphin,4-phenyl-perhydropyrrole(1,2-a)pyrazine-1,3-dione,alpha-hexachlorocyclohexane, abecarnil, tramiprosate, thioperamide, DN1417, remacemide, bemethyl, taglutimide,N-(4,4-diphenyl-3-butenyl)nipecotic acid, gaboxadol, ZK 93423, PD117302, ZK 93426, indeloxazine, milacemide, primidone, ZK 91296,ezogabine, kavain, vanillin, neurotropin, fosphenytoin, zaleplon, CGP39551, 2-amino-7-phosphonoheptanoic, 2-amino-4-phosphonobutyric acid,3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid,2-amino-4-methyl-5-phosphono-3-pentenoic acid, rimcazole, angelicin,tiagabine, levetiracetam, zonisamide, paraldehyde,2,3-piperidinedicarboxylic acid,6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione,eslicarbazepine acetate, vigabatrin,1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydroimidazol-2-one, glutamicacid diethyl ester, fludiazepam, gidazepam, ethotoin, mephobarbital,acetazolamide, NNC 711, indol-3-yl pyruvic acid, rufinamide, topiramate,clonazepam, tiletamine, riluzole, progabide, deramciclane, doramectin,chlormethiazole, L 701324, clorazepate dipotassium, lacosamide,thiopental, valproic acid, felbamate,2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline, 7-nitroindazole, GYKI52466, phenazepam, 4-amino-3-phenylbutyric acid, eperisone, sidnocarb,ryodipine, nimetazepam, nitrazepam, meprobamate, clobazam, estazolam,lorazepam, benzobarbital, magnesium sulfate, tizanidine, lamotrigine,flunarizine, pregabalin, gabapentin, phenytoin, phenobarbital,oxcarbazepine, carbamazepine, medazepam, pharmaceutically acceptablesalts thereof, and mixtures of any of the foregoing.

In certain embodiments, the additional antileptic drug administeredalong with ganaxolone is selected from the group consisting ofbenzodiazepines, phenytoin, fosphenytoin, valproic acid, phenobarbital,and/or levetiracetam.

In certain embodiments, the additional antiepileptic drug is abenzodiazepine (e.g., diazepam, lorazepam, etc.).

F. Definitions

All publications and patents cited in this disclosure are incorporatedby reference in their entirety. To the extent the material incorporatedby reference contradicts or is inconsistent with this specification, thespecification will supersede any such material. The citation of anyreferences herein is not an admission that such references are prior artto the present disclosure. When a range of values is expressed, itincludes embodiments using any particular value within the range.Further, reference to values stated in ranges includes each and everyvalue within that range. All ranges are inclusive of their endpoints andcombinable.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item.

The term “about” is used synonymously with the term “approximately.” Theuse of the term “about” with respect to doses and amounts of ganaxolonerefers to values slightly outside the cited values, i.e., plus or minus0.1% to 20%. The use of the term “about” with respect to time periods ofadministration means, for the purposes of the present invention, tocomprise 2 hours before and 2 hours after that time period. For example,a time period of “about 6 hours” encompasses a time period of 4 hoursand a time period of 8 hours. The term “about” with respect to a recitedpharmacokinetic parameter value (e.g., a plasma concentration) or arange of pharmacokinetic parameters values (e.g., a range of plasmaconcentrations values) encompass pharmacokinetic parameters and rangeswithin 80% to 120% of the recited value or range.

An “active agent” is any compound, element, or mixture that whenadministered to a subject alone or in combination with another agentconfers, directly or indirectly, a physiological effect on the patient.When the active agent is a compound, salts, solvates (includinghydrates) of the free compound or salt, crystalline and non-crystallineforms, as well as various polymorphs of the compound are included.Compounds may contain one or more asymmetric elements such asstereogenic centers, stereogenic axes and the like, e.g. asymmetriccarbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates oroptically active forms. For compounds with two or more asymmetricelements, these compounds can additionally be mixtures of diastereomers.For compounds having asymmetric centers, it should be understood thatall of the optical isomers in pure form and mixtures thereof areencompassed. In addition, compounds with carbon-carbon double bonds mayoccur in Z- and E-forms, with all isomeric forms of the compounds beingincluded in the present invention. In these situations, the singleenantiomers, i.e. optically active forms, can be obtained by asymmetricsynthesis, synthesis from optically pure precursors, or by resolution ofthe racemates. Resolution of the racemates can also be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralHPLC column.

As used herein, the term, “antiepileptic” is a synonym of the term“antiseizure” and means a medication that is used to control seizuresand/or epilepsy. The term “antiepileptic” encompasses anticonvulsantmedications (i.e., medications that that prevent, stop, or lessensconvulsions) and medications that prevent epileptic seizures.

As used herein, the term “Acute Repetitive Seizures” (ARS) refers to acondition manifested by multiple seizures occurring over a relativelybrief period of time—generally 24 hours—in patients with epilepsy. ARScould be convulsive or non-convulsive. ARS could progress in SE, buttypically there is a recovery period (break) between the seizures and/orconvulsions.

The abbreviation “EEG” means electroencephalography.

The terms “serum” and “plasma” as disclosed herein may be usedinterchangeably.

The term “intravenous bolus” is a relatively large dose of medication(e.g., ganaxolone) administered in a short period, for example within 1to 60 minutes (e.g., 3 or 5 minutes).

The term “Cmax” refers to the concentration of ganaxolone in the plasmaat the point of maximum concentration.

The abbreviation “eIND” means emergency treatment Investigational NewDrug Application.

The abbreviation “GNX” means ganaxolone.

“Ganaxolone” means 3α-hydroxy-3β-methyl-5α-pregnan-20-one.

“Infusion” administration is a non-oral administration, typicallyintravenous, though other non-oral routes such as epiduraladministration are included in some embodiments. Infusion administrationoccurs over a longer period than a bolus administration, for example fora time period greater than 1 hour (e.g., from about 1 hour to about 120hours).

The term “subject” as used herein refers to a human in need of medicaltreatment for status epilepticus.

“Pharmaceutical compositions” are compositions comprising at least oneactive agent, such as a compound or salt, solvate, or hydrate ofganaxolone, and at least one other substance, such as a carrier.Pharmaceutical compositions optionally contain one or more additionalactive agents. When specified, pharmaceutical compositions meet the U.S.FDA's GMP (good manufacturing practice) standards for human or non-humandrugs. “Pharmaceutical combinations” are combinations of at least twoactive agents which may be combined in a single dosage form or providedtogether in separate dosage forms with instructions that the activeagents are to be used together to treat a disorder, such as statusepilepticus.

The term “status epilepticus” (SE) is defined as a prolongedself-sustaining seizure or recurrent seizures without recovery ofconsciousness between seizures (Lowenstein and Alldredge, 1998). TheInternational League Against Epilepsy further defined SE as a conditionresulting either from the failure of mechanisms responsible for seizuretermination or from the initiation of mechanisms, which lead toabnormally, prolonged seizures (5 minutes for tonic-clonic SE and 10minutes for focal SE with impaired consciousness) and which can havelong-term consequences (after 30 minutes for tonic-clonic SE and after60 minutes for focal SE with impaired consciousness), including neuronaldeath and/or injury, and alteration of neuronal networks, depending onthe type and duration of seizures. SE encompasses a generalizedconvulsive status epilepticus (GCSE), non-convulsive status epilepticus(NCSE), early status epilepticus, established status eplilepticus (ESE),refractory status epilepticus (RSE), and super-refractory statusepilepticus (SRSE).

GCSE is defined as status epilepticus that is characterized byconvulsions that are associated with tonic-clonic movements of theextremities and mental status impairment, and may result in focalneurologic deficits lasting hours to days following an episode (Brophyet al, 2012). GCSE is associated with many complications, includingcardiac arrhythmias, rhabdomyolysis, pulmonary edema, electrolyte andglucose imbalance, and temperature disturbances.

NCSE is defined as status epilepticus in which seizure activity is seenon EEG without convulsive symptoms; however, acutely ill subjects maypresent with impaired mental status during an NCSE episode (Brophy etal, 2012).

RSE is defined as status epilepticus that failed to abort after afirst-line (i.e., a benzodiazepine) and a second-line anti-seizuremedication have been given. Duration is not part of the definition forRSE, which is based solely on the medications given and persistence ofseizures (Falco-Walter et al, 2016).

SRSE is defined as SE that continues 24 hours or more after the onset ofanesthesia, including those cases in which the SE recurs on thereduction or withdrawal of anesthesia’ (Shorvon and Ferlisi, 2011).

The term “seizure” or “an epileptic seizure” means a transientoccurrence of signs and/or symptoms related to abnormal, excessive orsynchronous neuronal activity in the brain. Seizures are detected in thebrain by measuring EEG activity. There can be seizures (in the brain)that will not be manifested as convulsions and can only be detected byEEG activity. The term “seizure activity” encompasses convulsions andEEG seizures.

A “taper period” is a period during which the continuous intravenousinfusion of ganaxolone is gradually lowered prior to the discontinuationof the intravenous infusion.

The term “therapeutically effective amount” as used herein refers to theamount of ganaxolone that is sufficient to stop or reduce severity ofstatus epilepticus or one or more of its symptom(s). For example, anamount for sufficient seizure suppression. The term “therapeuticallyeffective amount” includes, for example, a prophylactically effectiveamount. The effective amount of ganaxolone will be selected by thoseskilled in the art depending on the particular patient and the disease.It is understood that a therapeutically effective amount can vary fromsubject to subject, due to variation in metabolism of ganaxolone, age,weight, general condition of the subject, the condition being treated,the severity of the condition being treated, and the judgment of theprescribing physician.

As used herein, the terms “treat” or “treatment” refer to any to anyimprovement or any consequence of status epilepticus, such as reduced oreliminated seizure activity and/or reduced or eliminated convulsionsand/or completely suppresses status epilepticus (i.e., suppress EEGseizure activity and convulsions). As is readily appreciated in the art,full eradication of SE is preferred but albeit not a requirement for atreatment act. The treatment can be to cure, heal, alleviate, relieve,alter, remedy, ameliorate, palliate, improve or affect the disorder, thesymptoms of SE or the predisposition toward SE. For example, treatingmay achieve seizure suppression.

5. EQUIVALENTS

It will be readily apparent to those skilled in the art that othersuitable modifications and adaptions of the methods of the inventiondescribed herein are obvious and may be made using suitable equivalentswithout departing from the scope of the disclosure or the embodiments.Having now described certain compounds and methods in detail, the samewill be more clearly understood by reference to the following examples,which are introduced for illustration only and not intended to belimiting.

6. EXAMPLES

The present invention is further described by the following examples,which are not intended to be limiting in any way.

Example 1: Preliminary Clinical Evidence of Intravenous GanaxolonePharmacokinetics and Pharmacodynamics

A Phase I clinical trial evaluating IV ganaxolone formulation wasperformed. The clinical trial was designed to investigate the safety,pharmacokinetics, and pharmacodynamics of an intravenous bolus ofganaxolone and continuous intravenous infusion of ganaxolone in 30healthy subjects. Subjects were administered either an intravenous bolusof ganaxolone in an amount of 10-20 mg for a period of 2 minutes to 1hour, or an intravenous bolus of ganaxolone in an amount of 6 mg for aperiod of 5 minutes with a continuous intravenous infusion in an amountof 20 mg/hr for a period of 4 hours.

Pharmacokinetic analysis showed that all 30 healthy subjects treatedwith active ganaxolone had quantifiable ganaxolone levels in plasma andganaxolone concentrations in plasma were generally proportional to theadministered dose. Plasma concentrations that were achieved in thisstudy were in the range of those associated with a potentialanticonvulsant effect, based on historic data from subjects given oralganaxolone. Analysis of pharmacodynamic data showed that the bispectralindex (BIS) score correlated with estimated ganaxolone plasmaconcentrations at the time of BIS measurement. As expected, higherplasma concentration was associated with lower BIS scores (FIG. 1).There was little or no delay between the appearance of drug in plasmaand a change in the BIS score.

Example 2: Preliminary Clinical Evidence of Efficacy in Subject withStatus Epilepticus

Example 2 is an ongoing, double-blind, randomized, placebo-controlledPhase 2 study designed to evaluate the safety, tolerability, andefficacy of adjunctive IV GNX in subjects with SE who have failedinitial treatment with benzodiazepines and at least one AED. The studyconsists of a small open-label group to optimize the infusion parametersand provide a preliminary assessment of safety, efficacy, andtolerability of GNX administration, followed by a double-blind group whowill be randomized to receive GNX or placebo in a 1:1 ratio. In both theopen-label and double-blind groups, the study drug treatment isadjunctive therapy to standard of care, and subjects will receive astudy drug bolus dose with a concurrent continuous infusion treatmentwith the goal of administering a therapeutic dose as quickly as possibleto stop the seizures and prevent permanent neurological damage.Specifically, study drug will be added to the standard of care at thetime that the first 2nd-line IV AED has failed and the second 2nd-lineIV AED is medically indicated during the treatment of SE. Study drugmust be administered with the second-line IV AED as close to the doseinitiation of the second 2nd-line IV AED as possible, but before theinitiation of the third-line IV anesthetic for burst suppression.

Ganaxolone for this study is a proprietary IV formulation solubilized byCaptisol® (betadex sulfobutyl ether sodium). The maximum level ofCaptisol® will not exceed 50 g/per day. Ganaxolone for IV administrationwill be provided to the site as individual glass vials containing 3mg/mL of ganaxolone for the open-label group and 5 mg/mL of ganaxolonefor the double-blind group. Placebo for double-blind group IVadministration will be provided to the site as blinded matching vialscontaining 0.9% sodium chloride solution.

The primary objective of the study is to establish that IV GNX givenconcomitantly with second-line IV AED therapy is safe and effective instopping SE that has already failed at least one second-line IV AEDtherapy and prevents escalation of treatment requiring an IV anestheticdrug (a third-line treatment) for seizure suppression. Secondaryobjectives include assessment of mortality, seizure cessation insubjects with SE, and evaluation of pharmacokinetics of IV GNX insubjects with SE. Approximately 262 subjects will be enrolled across theopen-label and the double-blind groups.

Total adjunctive GNX therapy infusion treatment is planned to be 3 or 5days (including an 18-hour taper). All subjects will have a 3-minutebolus dose with a continuous infusion at the rate from about 10 mg/hourto about 85 mg/hour or from about 18 mg/hr to 80 mg/hr, and an 18-hourtaper. Once study drug administration is started it will be deliveredfor a full 2 or 4 days (48 or 96 hours) prior to tapering. At the end ofsecond day administration, the decision to administer the study drug foran additional 2 days (i.e., for a total of 4 days) will be made. If inthe investigator's medical judgment the subject will continuebenefitting from study drug administration, ganaxolone will beadministered to the additional 2 days.

Ganaxolone dose will be tapered prior to the discontinuation. To taperganaxolone after 2 or 4 days of treatment, the continuous infusion willbe reduced by 25% every 6 hours; 75%, 50%, 25% over 18 hours and thendiscontinued. If the infusion rate becomes too low during these 18-hoursto sustain the infusion line it can be discontinued at that point. It iscontemplated that, if a subject takes study drug for less than 2 hoursand/or requires an IV anesthetic drug (a 3rd line treatment) for seizuresuppression, they should be discontinued from the study drug without thestudy drug taper.

The following dosing schedule is planned.

Subjects Weighing at Least 40 kg:

A 25-mg bolus dose (over ˜3 minutes) will be administered with acontinuous infusion of 80 mg/hour for 2 hours followed by a continuousinfusion rate of 40 mg/hour for 6 hours, and then 18 mg/hour for theremaining 16 hours of Day 1. At the end of the first 24 hours ofcontinuous infusion (Day 1), the infusion rate will be increased to 29mg/hour for the remaining treatment, Day 2 (24-48 hours) or Day 2through 4 (24-96 hours).

TABLE 2 Dosing for Subjects ≥ 40 kg (on an mg/hour basis) Dose Level ofStudy Drug IV Days Start Time from Dose Initiation (infusion rate)Duration Day 1 0 hours: bolus dose via syringe or 25 mg 3 minutesinfusion pump Day 1 0 hours through 2 hours post-dose: 80 mg/hour 2hours continuous infusion, started with bolus Day 1 2 hours post-dosethrough 8 hours 40 mg/hour 6 hours post-dose Day 1 8 hours post-dosethrough 24 hours 18 mg/hour 16 hours post-dose Day 2 or Day 2 24 hourspost-dose through 48 hours 29 mg/hour 24-72 hours through Day 4 postdose (Day 2) or 24 hours post- (Day 2 or dose though 96 hours post-dose(Day Day 4) 2-4) Taper for subjects discontinuing study drug Day 3 orDay 5 48 or 96 hours post-dose: 18-hour Reduce infusion 6 hours taperrate by 25% Reduce infusion 6 hours rate by 25% Reduce infusion 6 hoursrate by 25%

Subjects Weighing <40 kg Will be Dosed on a Per-Kilogram Basis:

A 0.375-mg/kg bolus dose (over ˜3 minutes) will be administered with acontinuous infusion of 1.2 mg/kg/hour for 2 hours followed by acontinuous infusion rate of 0.6 mg/kg/hour for 6 hours, and 0.27mg/kg/hour for the remaining 16 hours of Day 1. At the end of the first24 hours of continuous infusion (Day 1), the infusion rate will beincreased to 0.435 mg/kg/hour for the remaining treatment period, Day 2(24-48 hours) or Day 2 through 4 (24-96 hours).

TABLE 3 Dosing for Subjects < 40 kg (on an mg/kg/hour basis) Dose Levelof Days Start Time from Dose Initiation Study Drug Duration Day 1 0hours: bolus dose via syringe or 0.375 mg/kg 3 minutes infusion pump Day1 0 hours through 2 hours post-dose: 1.2 mg/kg/hour 2 hours continuousinfusion, started with bolus Day 1 2 hours post-dose through 8 hours 0.6mg/kg/hour 6 hours post-dose Day 1 8 hours post-dose through 24 hours0.27 mg/kg/hour 16 hours post-dose Day 2 or Day 2 24 hours post-dosethrough 48 0.435 mg/kg/hour 24-72 hours through Day 4 hours post dose(Day 2) or 24 (Day 2 or hours post-dose though 96 hours Days 2-4)post-dose (Days 2-4) Taper for subjects discontinuing study drug Day 3or Day 5 48 or 96 hours post-dose: 18-hour Reduce infusion 6 hours taperrate by 25% Reduce infusion 6 hours rate by 25% Reduce infusion 6 hoursrate by 25%

These infusion dosing parameters are expected to result in daily dosesof ganaxolone of about ≤714 mg/day and Captisol of about ≤50 grams/day.Based on PK modeling, it is predicted that maximum concentrations ofganaxolone should remain within 1,000 ng/mL during infusion, but somevariability is expected due to, for example, differences in subjects'weight.

As of 22 Mar. 2019, 5 subjects were enrolled into the Study 1042-SE-2001open-label group under the original protocol that limits daily Captisolexposure at 35 g/day. In all 5 cases, the initial 3-minute bolus dose of30 mg GNX with concurrent continuous infusion at 85 mg/hr for 2 hoursfollowed by 40 mg/hr for 2 hours of GNX infusion resulted in theimmediate cessation of seizures as evidenced by EEG activity in subjectswith SE that was otherwise resistant to several second line IV AEDsconsidered standard-of-care. The initial EEG pattern post-infusioninitiation was described by study physicians as a “light” burstsuppression that was maintained for several hours in all subjects.Although some subjects required intubation for airway protection, nosubjects had to be intubated as a direct result of GNX therapy. Inaddition, no GNX-related cardiovascular events that requiredpharmacological intervention were observed. It was observed that whenGNX exposure was lowered (20 mg/hr for 2 hours and ending with 10 mg/hrfor the remaining 18 hours on Day 1) in order not to exceed this limit,seizure control could not be maintained and seizure activity (but notSE) re-occurred as evidenced by EEG changes. Pharmacokinetic modelingdata (FIG. 2) from these 5 subjects suggested that exposure levels ofGNX at approximately 1000 ng/mL were associated with rapid and completeSE suppression, and lower GNX exposures at <500 ng/mL were associatedwith seizure relapse. Seizure activity relapsed when plasmaconcentrations of GNX decreased <500 ng/mL in 4 out of 5 subjects.

Case reports of the 5 subjects are presented below.

1. Subject 004-101

Subject 004-101 was a 75-year-old female who presented with a subduralhematoma due to a fall (Day 1). Levetiracetam was started. Uponphysician exam, the subject was noted to be lying in the bedunresponsive to both verbal and noxious stimuli. Pupils were equal,round, and reactive to light, no corneal, no gag, and vestibulo-occularreflex was intact. Blood pressure and saturation were stable. Due to themental status change, the decision was made to intubate the subject forairway protection. On Day 3, EEG showed partial seizures and additionalinfusions of levetiracetam were given, followed by multiple infusions oflacosamide. During the study enrollment discussion, the family reportedthat the subject was slow to come out of anesthesia in the past.

On Day 3, IV GNX was administered starting with a 30 mg bolus over 3minutes and a continuous infusion of 85 mg/hr for 2 hours. Almostimmediately the EEG showed seizure suppression, with the EEG patterndescribed as by the Principal Investigator as, “putting the subject inweak burst suppression.” During the second hour of treatment the studydrug administration was interrupted for 14 minutes while the subject wasintubated for airway protection. The intubation was not consideredrelated to the study drug; the decision to intubate was made beforestarting GNX infusion. The continuous infusion was restarted withoutincident. Dosing continued per protocol with infusion rate reductions to40 mg/hr at 2 hours post-dose, 20 mg/hr at 4 hours post-dose, and 10mg/hr at 6 hours post dose. Seizure relapse occurred at approximately 5hours post infusion start, at which time the subject was receiving GNXat a 20 mg/hr infusion rate. GNX was discontinued on Day 2. Thesubject's GNX plasma concentration was <500 ng/mL at the time of seizurerelapse (FIG. 3). A snapshot of the subject's EEG patterns prior to andafter initiation of GNX is provided in FIG. 4.

2. Subject 004-102

Subject 004-102 was a 43-year-old female with a history of seizures whopresented in NCSE (Day 1). Prior AED medications included lamotrigine.The subject was intubated and given a single dose of fosphenytoinfollowed by levetiracetam. On the same day, IV GNX 30 mg bolus was givenover 3 minutes and the continuous infusion (85 mg/hr) was initiated.There was no seizure activity noted on EEG at 60 minutes and 2 hourspost-dose initiation. As per the protocol, GNX was decreased to 40mg/hr, 20 mg/hr, and 10 mg/hr sequentially. The 10 mg/hr was continuedfor the remaining 18 hours of Day 1. The subject continued to be seizurefree; however, a concerning EEG pattern returned between 5 to 6 hourspost-dose initiation, at which time the subject was receiving GNX at a20 mg/hr infusion rate. The subject's GNX plasma concentration at thetime of seizure relapse is shown in FIG. 5. A return of an EEG patternoccurred around the same timeframe and it evolved over the next 48 hoursand required additional intervention approximately 42.5 hours post-doseinitiation while the subject was receiving GNX at a 20 mg/hr infusionrate. GNX was discontinued on Day 2. A snapshot of the subject'squalitative EEG patterns prior to and after initiation of GNX isprovided in FIG. 6.

3. Subject 006-101

Subject 006-101 was a 59-year-old female who presented in NCSE, etiologyunknown (Day 1). Subject was unresponsive to verbal and physicalstimuli. A single dose of lacosamide was given and subject was intubatedfor airway protection. EEG showed epileptiform discharges associatedwith obtundation and limb switches, and was subject was given lorazepamdose with no improvement. On the same day, IV GNX 30 mg bolus was givenand the continuous infusion (85 mg/hr) was initiated. Per site report,the SE aborted within 1 minute of the bolus administration. There was noseizure activity noted on EEG at 60 minutes and 2 hours post-doseinitiation. Per the protocol, GNX was sequentially decreased to 40mg/hr, 20 mg/hr, and 10 mg/hr. Seizure relapse occurred at approximately6 hours post infusion start, at which time the subject was receiving GNXat a 20 mg/hr infusion rate. GNX taper was initiated on Day 4. Thesubject's GNX plasma concentration was <500 ng/mL at the time of seizurerelapse (FIG. 7). A snapshot of the subject's EEG patterns prior to andafter initiation of GNX is provided in FIG. 8.

The SE relapse occurred while the subject's infusion rate was 10 mg/hr.The two adjacent PK sample results were within the low predicted valuesfor the infusion rate. It was confirmed that PK samples were collectedfrom the infusion site. It was confirmed that the correct analysisprocedures where performed by the bioanalytical laboratory.

4. Subject 006-102

Subject 006-102 was an 88-year-old female with a history of seizures anddementia who was transferred from a nursing home after having been foundby her daughter with altered mental status and inability to verbalizeher complaints (Day 1). The family confirmed that the subject had fallenand possibly hit her head the previous week. Subdural hematoma (1.4 cm)was identified on computed tomography (CT) scan. Subject was intubated,placed on propofol, and transferred from the remote hospital to thestudy site where she was prepared for evacuation of the subduralhematoma. Propofol was stopped. During physical examination, thesubject's eyes opened spontaneously, the pupils were equal round, andreactive to the light. She followed simple commands and moved all theextremities spontaneously. The subject was administered single doses oflevetiracetam on Day 1 and Day 4 and twice daily dosing on Day 3. Threesingle doses of lorazepam were administered on Day 5 prior to GNXadministration along with multiple doses of levetiracetam and a singledose of lacosamide. On Day 5, the subject had worsening neurologicalexam and CT of the head showed signs of stroke on the right cerebralhemisphere. On the same day, an EEG confirmed a diagnosis of NCSE atwhich time the subject was enrolled in the clinical study and started onIV GNX 30 mg bolus dose plus continuous infusion (85 mg/hr). Per sitereport, the SE aborted upon administration of the bolus GNXadministration. There was no seizure activity noted on EEG at 60minutes, 2 hours, and 4 hours post-dose initiation. Per the protocol,GNX was sequentially decreased to 40 mg/hr, 20 mg/hr, and 10 mg/hr.Seizure relapse occurred at approximately 6 hours post infusion start,at which time the subject was receiving GNX at a 20 mg/hr infusion rate.GNX taper was initiated on the fourth day of GNX therapy. The subject'sGNX plasma concentration was <500 ng/mL at the time of seizure relapse(FIG. 9).

5. Subject 015-101

Subject 015-101 was a 24-year-old female who presented with focalconvulsive SE due to a tumor (Day 1). Recent medical history includedconvulsive seizures, SE, and Glioblastoma multiform of parietal lobe.Subject was administered levetiracetam for SE and lorazepam, diazepam,dexamethasone, and multiple doses of levetiracetam for seizure controlprior to study enrollment. On Day 3, the subject was enrolled in thestudy and started on IV GNX 30 mg bolus dose plus continuous infusion(85 mg/hr). At the start of dose initiation the subject was alert.Shortly after the bolus started the subject developed significantsomnolence. She was arousable to voice but required continuousstimulation to stay awake or follow commands. She maintained her airwayand was able to endorse that the numbness had resolved and reported thatshe no longer felt twitches. She had a feeling of impending doom anddeath. The subject had significant direction-changing nystagmus andcomplained of blurry vision. At the same time she developed urinaryretention with urgency. The bladder scanner demonstrated at least 750 mLof urine and Foley catheter was placed. During the next 2 hours thesubject remained somnolent and was becoming increasingly restless. Asper the protocol, GNX was decreased to 40 mg/hr at 2 hours post doseinitiation. Approximately 10 to 15 minutes after the infusion rate wasdecreased to 40 mg/hr, the subject's arousal improved, she becameconversational, and wanted to eat. She had no seizures at this time.Vital signs remained stable. During the GNX infusion, concomitantlacosamide was increased due to increased numbness. Seizures did notreturn during the treatment period and the investigator tapered thestudy drug per the protocol after 2 days. Once the GNX taper wascompleted the investigator reported there were no sequelae. Thesubject's GNX plasma concentration over time is provided in FIG. 10.

In summary, all 5 subjects showed immediate cessation of SE with theinitiation of the initial bolus plus continuous infusion dose. Based onthese data, the United States Food and Drug Administration (FDA) allowedthe daily limit of Captisol exposure to increase to 50 g/day (and thetotal daily dose of GNX to increase from 500 to 715 mg), therebyallowing for GNX exposure to be maintained at >500 ng/ml forapproximately 8 hours.

Under the protocol amended with the 50 g/day Captisol limit, 1 subjectwas enrolled in the open-label study as of 26 Mar. 2019. The malesubject presented with NCSE due to a tumor. The subject failed 3second-line IV AEDs and qualified for the study based on the study'sinclusion/exclusion criteria. Within 3 minutes after starting the IV GNXinfusion, the RSE ceased and seizure protection was maintained for theremaining 48 hours of GNX treatment. The subject was successfully weanedoff GNX (i.e., no seizure relapse). Based on the preliminary assessment,the only safety finding related to GNX was an increased sedation (likelydue to a concomitant use of GNX with several AEDs with CNS-depressantproperties as part of standard of care anti-seizure therapy).Pharmacokinetic data were unavailable at the time of this report.

In addition, GNX has been administered to 2 subjects with SRSE underseparate emergency treatment INDs (eINDs).

Under eIND No. 131,642, IV GNX was administered to a subject with SRSEwho was unable to maintain status cessation with ketamine andbarbiturates. The Day 1 dosage regimen delivered 900 mg of GNX, equatingto a 900 to 1200 ng/mL plasma concentration of GNX. As the subject couldnot be maintained in burst suppression, the clinical team was able toutilize EEG changes to gauge the response (FIG. 11). The effect of GNXstarted at 60 mg/hr dose and resulted in complete seizure cessation atthe 120 mg/hr dose. However, due to the dosing plan agreed upon with theFDA with a daily Captisol limit of 63 g/day, the initial 120 mg/hr doseon Day 1 could not be maintained for longer than 1 hour and then had tobe decreased to the 30 mg/hr dose. The first seizures re-occurred within15 to 20 minutes of the change in GNX dose from 120 mg/hr to 30 mg/hr.

Additionally, under eIND No. 137,883, IV GNX was administered to apediatric subject with SRSE who had previously failed treatment withlevetiracetam, topiramate, clobazam, phenobarbital, rufinamide,perampanel, pentobarbital, and ketamine. At the time of the eIND, nopediatric pharmacokinetic data was available for the IV formulation ofGNX. The dose regimen (GNX initiated at 75 mg/hr and rate decreased to40 mg/hr 1 hour later) was based on plasma drug concentration levelsmeasured in adults and designed to achieve a plasma drug concentrationof approximately 1000 ng/mL within 1 hour and hold that level for 23additional hours. At the time of GNX initiation, the subject wasintubated and receiving pentobarbital at a rate of 2.25 mg/kg/hr. At thetime of the GNX bolus infusion, the EEG showed a continuous suppressedbackground. This activity lasted for approximately 2 hours at whichpoint the pentobarbital was decreased to 1 mg/kg/h. On examination thesubject had nonreactive pupils and GNX infusion was stopped.

With these encouraging data, Marinus received permission from the U.S.FDA to increase daily Captisol limits from 35 to 50 g/day. One subjectunder the increased Captisol daily limit experienced rapid RSE cessationfollowing GNX treatment despite failing 3 second-line IV AEDs and wassuccessfully weaned off GNX without seizure relapse.

This study is ongoing and once completed will be used to design thepivotal Phase 3 study in subjects with RSE.

Example 3: Phase 2 Open-Label Dose Range Study

An open-label, dose range finding study in which IV ganaxolone was addedto standard-of-care IV AEDs in SE patients who had failed initialbenzodiazepines and at least one 2nd line IV AED but had not progressedto IV anesthetics was performed. The primary objective of the study wasto establish that IV ganaxolone was safe and effective when added tostandard of care IV AED therapy in stopping SE and preventing theescalation of treatment to IV anesthesia for seizure suppression.Secondary objectives included assessment of adverse events andevaluation of the pharmacokinetics of IV ganaxolone in patients with SE.

Eligible patients were treated with continuous adjunctive IV ganaxoloneinfusion. Initial dosing included a 3-minute bolus dose (25 or 30 mg)with a continuous infusion at rates ranging from 10 to 85 mg/hour for upto 96-hours, followed by an 18-hour study drug taper.

The study enrolled 17 patients divided among 3 dosing cohorts. The IVsolution utilizes Captisol® as an excipient for solubilization ofganaxolone. In an agreement with the Food and Drug Administration (FDA),the Captisol exposure for patients participating in Study 1042-SE-2001was not to exceed 50 g/day. Given the daily Captisol limit, 3 differentdoses of GNX IV solution were investigated; 500, 650, and 713 mg/daytotal GNX referred to as the low, medium, and high dose level cohorts,respectively.

The details on the infusion parameters during the firsts 24 hours foreach of the dose groups are provided below:

TABLE 4 Infusion parameters for each dose cohort Dose Cohort Dose Lowdose 30 mg bolus, 85 mg/hr for 2 hours, 40 mg/hr for 2 hours, 20 mg/hrfor 2 hours, and 18 mg/hr for 18 hours Medium dose 25 mg bolus, 35 mg/hrfor 12 hours, 25 mg/hr for 4 hours, and 13 mg/hr for 8 hours High dose25 mg bolus, 80 mg/hr for 2 hours, 40 mg/hr for 6 hours, and 18 mg/hrfor 16 hours.

The major difference between the low and high dosing cohorts was theduration of predicted plasma GNX levels>500 ng/ml (4 vs. 8-hours,respectively). The major differences between the medium and low/highdose cohorts was the duration of initial predicted plasma levels ofGNX>700 ng/mL (minutes vs. 2-hours, respectively) and that the predictedplasma levels of GNX in the medium dose cohort never exceeded 500 ng/mL.The predicted 24-hr GNX plasma concentrations associated with eachdosing cohort are shown in FIG. 14.

The number of patients enrolled into each of the three dose levelcohorts are presented in table 5 below.

TABLE 5 Participant enrollment in the study Number of Duration ≥500Participants Cohort Dose of GNX/day ng/ml Enrolled Low 500 mg/day 4hours 5 Medium 650 mg/day 0 hours 4 High 713 mg/day 8 hours 8 GNX =ganaxolone

Preliminary results from this open-label, dose-finding Study1042-SE-2001 in RSE patients showed that all patients (100%; n=17) didnot require escalation of treatment to an IV anesthetic drug for SEcontrol within the first 24-hours after initiation of GNX treatment,thereby meeting the primary endpoint. 16 patients (94%) achieved andmaintained SE cessation within the first 24-hours following initiationof GNX treatment. 14 patients (82%) did not require additional IV AEDSor IV anesthetics for status relapse up to 4 weeks. A summary isprovided below in Table 6.

TABLE 6 Preliminary results from open-label, dose-finding study in RSEpatients No escalation to additional IV AEDs or IV No escalation toanesthetics for IV anesthetics status relapse No SE Relapse within 24hrs Status-free at any time at anytime from infusion through 24 hrsthrough 24 hrs during the 4- initiation(Primary from infusion after GNXwk follow up Cohort Endpoint) initiation discontinuation period Target100%  88% 100%  100%  (713 mg/day) (8 of 8) (7 of 8) (8 of 8) (6 of 6)(n = 8) (1ET, 1 died) Medium 100% 100% 75% 67% (650 mg/day) (4 of 4) (4of 4) (3 of 4) (2 of 3) (n = 4) (1 ET) Low 100% 100% 60% 50% (500mg/day) (5 of 5) (5 of 5) (3 of 5) (1 of 2) (n = 5) (1 died)

Median time to SE cessation was 5 minutes from initiation of GNXtreatment (n=15 evaluable patients). FIG. 12. In 14 out of 15 patients,SE cessation was achieved in <30 min.

IV GNX achieved a rapid and dose-dependent sustained reduction in EEGseizure burden in 15 evaluable patients (FIG. 15).

Acute maintenance of GNX plasma concentrations >500 ng/mL was associatedwith improved seizure control on EEG (FIGS. 13A-13D).

GNX infusion was generally well-tolerated in this patient population andthe safety profile of GNX was consistent with its GABAergic mechanism ofaction. SAEs (severe sedation) assessed as related to GNX treatment werereported in 2 participants that led to early GNX discontinuation. These2 cases occurred in participants who were concomitantly receivingseveral other CNS depressant medications and did not occur at the timeof the highest predicted plasma concentrations of GNX.

1-54. (canceled)
 55. A method of treating status epilepticus (SE),comprising administering to a subject in need thereof an effectiveamount of ganaxolone to suppress SE for a period of at least 8 hours,wherein the effective amount of ganaxolone is administered as anintravenous bolus plus continuous infusion to produce and maintain aganaxolone plasma concentration of at least about 500 ng/ml for at leastabout 8 hours.
 56. The method of claim 55, wherein the intravenous boluscomprises about 5 mg to about 40 mg of ganaxolone.
 57. The method ofclaim 56, wherein the intravenous bolus comprises about 30 mg ofganaxolone.
 58. The method of claim 55, wherein the continuousintravenous infusion comprises infusion of about 20 mg of ganaxolone perhour to about 80 mg of ganaxolone per hour.
 59. The method of claim 58,wherein about 80 mg of ganaxolone per hour are infused into the subjectat the initiation of the continuous intravenous infusion and for atleast about 2 hours thereafter.
 60. The method of claim 59, wherein theamount of ganaxolone infused into the subject by the continuousintravenous infusion is decreased from about 80 mg per hour to about 40mg per hour after about 2 hours.
 61. The method of claim 60, wherein the40 mg per continuous intravenous infusion is administered for about 6hours to about 10 hours.
 62. The method of claim 61, wherein the amountof ganaxolone infused into the subject by the continuous intravenousinfusion is then decreased from about 40 mg per hour to about 20 mg perhour.
 63. The method of claim 62, wherein the 20 mg per hour continuousintravenous infusion is administered for about 12 hours to about 24hours.
 64. The method of claim 55, wherein a continuous intravenousinfusion of ganaxolone is initiated periprocedurally with theintravenous bolus and the continuous intravenous infusion comprises: a)an infusion of about 80 mg ganaxolone per hour for about 2 hours, thenb) an infusion of about 40 mg ganaxolone per hour for about 6 hours toabout 10 hours, then c) an infusion of about 20 mg ganaxolone per hourfor about 12 hours to about 24 hours, and optionally wherein the 20 mgper hour infusion is increased to up to 45 mg per hour starting at about24 hours after initiating the continuous intravenous infusion for up toabout 12 hours.
 65. The method of claim 55, wherein the intravenousbolus produces a ganaxolone plasma concentration in the subject of atleast about 500 ng/ml to about 1000 ng/ml.
 66. The method of claim 55,wherein the continuous intravenous infusion produces a ganaxolone plasmaconcentration in the subject of at least about 500 ng/ml to about 1000ng/ml for at least about 8 hours.
 67. The method of claim 55, whereinthe intravenous bolus is administered to the subject for about 1 minuteto about 5 minutes.
 68. The method of claim 64, wherein the continuousintravenous infusion is administered for at least about 8 hours to about36 hours after the initiation of the continuous intravenous infusion.69. The method of claim 68, wherein the treatment period is about 36hours after the initiation of the continuous intravenous infusion. 70.The method of claim 64, further comprising a taper period for about 12hours, wherein the taper period starts at about 36 hours from theinitiation of the continuous intravenous infusion.
 71. The method ofclaim 55, wherein the intravenous bolus plus continuous infusionproduces and maintains a ganaxolone plasma concentration of at leastabout 500 ng/ml for at least about 8 hours to about 12 hours.
 72. Themethod of claim 55, wherein the subject as refractory statusepilepticus.
 73. The method of claim 55, wherein the bolus plus thecontinuous infusion results is a reduction of seizure burden to about20% or less, or a reduction of seizure burden of at least about 50%relative to the seizure burden during the 30 minutes immediately priorto administration of the bolus.
 74. The method of claim 73, wherein thereduction of seizure burden persist for at least about 8 hours to about12 hours.